Method for treatment of non-rheumatoid arthritis

ABSTRACT

A method is disclosed for the treatment of non-rheumatoid arthritis by administering to a mammal in need thereof a therapeutically effective amount of an sPLA 2  inhibitor.

This application is a 371 of PCT/US98/17778 filed Aug. 27, 1998, andclaims the benefits of No. 60/057,726, filed Aug. 28, 1997.

FIELD OF THE INVENTION

The present invention is directed to a method for treatingnon-rheumatoid arthritis. More specifically, the present invention isdirected to a method for treating the causes and/or the symptoms ofvarious forms of non-rheumatoid arthritis in mammals by administering atherapeutically effective amount of an sPLA₂ inhibitor.

BACKGROUND OF THE INVENTION

“Arthritis” is the name given to disease states encompassing manydifferent conditions frequently having entirely different symptoms,causes, and known treatments. Although, the word “arthritis” means jointinflammation, it has come to encompass disorders that affect not onlythe joints but other connective tissue of the body including supportingstructures such as muscles, tendons, and ligaments as well as theprotective coverings of internal organs. Some of the most commonlyoccurring forms of arthritis are osteoarthritis, ankylosing spondylitis,rheumatic fever, and gout. Some forms of inflammatory arthritis arecharacterized by lymphokine-mediated inflammation of the joints. The useof selected secretory phospholiase A2 (sPLA₂) inhibitors to treatrheumatoid arthritis is described in European Patent No. 0675110(published Oct. 4, 1995) and in U.S. Pat. No. 5,654,326.

The most common form of non-rheumatoid arthritis is osteoarthritis, adegenerative joint disease which primarily affects cartilage that coversand cushions the ends of the bones causing it to fray, wear, ulcerate,and in extreme cases, to disappear entirely leaving a bone on bonejoint. The disease can result in severe disability particularly in theweight bearing joints such as the knees, hips, and spine. Osteoarthritisis distinguishable, for example, from rheumatoid arthritis in thatosteoarthritis involves little or no inflammation and is confined to thejoints and surrounding tissue where there is a breakdown ordisintegration of cartilage and other tissue thereby making it difficultfor the joints to operate properly. The occurrence of osteoarthritisfrequently increases with advancing years.

Non-rheumatoid arthritis is often treated with acetaminophen andibuprofen. In addition, non-steroidal anti-inflammatory drugs (NSAIDSs)may be used to relieve pain by blocking the production of prostaglandins(e.g., choline magnesium salicylate, salicylsalicyclic acid).Corticosteroids such as methylprednisone, prednisone, and cortisone maybe used to relieve pain and swelling. Each of these known drug therapieshas possible long-term disadvanges such as kidney or liver damage,heartburn, stomach upset, ulcers, gastrointestinal bleeding, moodswings, weight fain, high blood pressure, muscle weakness and loweredresistance to infection.

Accordingly, there is a substantial need for a novel effective, and easyto administer treatment for forms of arthritis which arenon-inflammatory and/or non-rheumatoid such as the most common form ofarthritis, osteoarthritis, as well as the many other forms of thedisease which occur. It is therefore an object of the present inventionto provide a methodology for effectively treating non-rheumatoidarthritis.

SUMMARY OF THE INVENTION

The method of this invention comprising administering to a mammal,including a human, having non-rheumatoid arthritis, a therapeuticallyeffective amount of an sPLA₂ inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term “non-rheumatoid arthritis” as used herein includes a widevariety of disease states limited to those listed as (1) thru (10) belowand is intended to specifically exclude rheumatoid arthritis, ordiseases whose major component is believed to be rheumatoid arthritis.The primary disease state to be defined by the term, “non-rheumatoidarthritis” is osteoarthritis.

Types of Non-rheumatoid Arthritis

1. Osteoarthritis

2. Gout

3. Spondylarthropathris

a. ankylosing spondylitis

b. Reiter's syndrome

c. Psoriatic arthropathy

d. Enterapathric spondylitis

e. Juvenile arthropathy or juvenile ankylosing spondylitis

f. Reactive arthropathy

4. Infectious or post-infectious arthritis

a. Gonoccocal arthritis

b. Tuberculous arthritis

c. Viral arthritis

d. Fungal arthritis

e. Syphlitic arthritis

f. Lyme disease

5. Arthritis associated with “vasculitic syndromes”

a. polyarteritis nodosa

b. hypersensitivity vasculitis

c. Luegenec's granulomatosis

d. polymyalgin rheumatica

e. joint cell arteritis

6. Calcium crystal deposition arthropathies

a. pseudo gout

7. Non-articular rheumatism

a. bursitis

b. tenosynomitis

c. epicondylitis (tennis elbow)

d. carpal tunnel syndrome

e. repetitive use injury (typing)

8. Miscellaneous forms of arthritis

a. neuropathic joint disease (charco and joint)

b. hemarthrosis (hemarthrosic)

c. Henoch-Schonlein Purpura

d. hypertrophic osteoarthropathy

e. Multicentric reticulohistiocytosis

9. Arthritis associated with certain diseases

a. surcoilosis

b. hemochromatosis

c. sickle cell disease and other hemoglobinopathries

d. hyperlipo proteineimia

e. hypogammaglobulinemia

f. hyperparathyroidism

g. acromegaly

h. familial Mediterranean fever

i. Behat's Disease

j. Systemic lupus erythrematosis

k. hemophilia

10. Relapsing polychondritis

Definitions for 1H-indole-3-glyoxylamide Compounds

The term, “therapeutically effective amount” is a quantity of sPLA₂inhibitor sufficient to significantly alleviate symptoms characteristicof non-rheumatoid arthritis in a mammal in need thereof.

Other Definitions

The term, “mammal” includes humans.

The term, “parenteral” means not through the alimentary canal but bysome other route such as subcutaneous, intramuscular, intraorbital,intracapsular, intraspinal, intrasternal, or intravenous.

The term, “active compound” means one or more sPLA₂ inhibitors used inthe method of the invention.

I. sPLA₂ Inhibitors Useful in the Method of the Invention

Secretary phospholipase A2 (sPLA₂) inhibitors in general are useful inthe practice of the method of this invention. In particular, thisinvention teaches the use of mono- or poly-cyclic organic sPLA₂inhibitors having a molecular weight from 150 to 700 for treatment ofnon-rheumatoid arthritis. Preferably poly-cyclic organic sPLA₂inhibitors having at least one heterocyclic nitrogen atom and having amolecular weight from 250 to 600 are used by the method taught hereinfor treatment of non-rheumatoid arthritis.

Exemplary of classes of suitable sPLA₂ useful in the method of theinvention for treatment of non-rheumatoid are the following:

1H-indole-3-glyoxylamides

1H-indole-3-hydrazides

1H-indole-3-acetamides

1H-indole-1-glyoxylamides

1H-indole-1-hydrazides

1H-indole-1-acetamides

indolizine-1-acetamides

indolizine-1-acetic acid hydrazides

indolizine-1-glyoxylamides

indene-1-acetamides

indene-1-acetic acid hydrazides

indene-1-glyoxylamides

carbazoles & tetrahydrocarbazoles

pyrazoles

phenyl glyoxamides

pyrroles

naphthyl glyoxamides

phenyl acetamides

naphthyl acetamides

Each of the above sPLA₂ inhibitor types is discussed in the followingsection wherein details of their molecular configuration are given withdetails of their preparation.

a) The 1H-indole-3-glyoxylamide sPLA₂ inhibitors and method of makingthem are described in U.S. Pat. No. 5,654,326, the entire disclosure ofwhich is incorporated herein by reference. Another method of making1H-indole-3-glyoxylamide sPLA₂ inhibitors is described in U.S. patentapplication Ser. No. 09/105381, filed Jun. 26, 1998 and titled, “Processfor Preparing 4-substituted 1-H-Indole-3-glyoxyamides” the entiredisclosure of which is incorporated herein by reference. U.S. patentapplication Ser. No. 09/105,381 discloses the following process havingsteps (a) thru (i):

Preparing a compound of the formula I or a pharmaceutically acceptablesalt or prodrug derivative thereof

 wherein:

R¹ is selected from the group consisting of

 where

R¹⁰ is selected from the group consisting of halo, C₁-C₁₀ alkyl, C₁-C₁₀alkoxy, —S—(C₁-C₁₀ alkyl) and halo(C₁-C₁₀)alkyl, and t is an integerfrom 0 to 5 both inclusive;

R² is selected from the group consisting of hydrogen, halo, C₁-C₃ alkyl,C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl, —O—(C₁-C₂ alkyl), —S—(C₁-C₂alkyl), aryl, aryloxy and HET;

R4 is selected from the group consisting of —CO₂H, —SO₃H and —P(O)(OH)₂or salt and prodrug derivatives thereof; and

R⁵, R⁶ and R⁷ are each independently selected from the group consistingof hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,halo(C₂-C₆)alkyl, bromo, chloro, fluoro, iodo and aryl;

which process comprises the steps of:

a) halogenating a compound of formula X

 where R⁸ is (C₁-C₆)alkyl, aryl or HET;

 with SO₂Cl₂ to form a compound of formula IX

b) hydrolyzing and decarboxylating a compound of formula IX

 to form a compound of formula VIII

c) alkylating a compound of formula VII

 with a compound of formula VIII

 to form a compound of formula VI

d) aminating and dehydrating a compound of formula VI

 with an amine of the formula R¹NH₂ in the presence of a solvent thatforms and azeotrope with water to form a compound of formula V;

e) oxidizing a compound of formula V

 by refluxing in a polar hydrocarbon solvent having a boiling point ofat least 150° C. and a dielectric constant of at least 10 in thepresence of a catalyst to form a compound of formula IV

f) alkylating a compound of the formula IV

 with an alkylating agent of the formula XCH₂R^(4a) where X is a leavinggroup and R^(4a) is —CO₂R^(4b), —SO₃R^(4b), —P(O)(OR^(4b))₂, or—P(O)(OR^(4b))H, where R^(4b) is an acid protecting group to form acompound of formula III

g) reacting a compound of formula III

 with oxalyl chloride and ammonia to form a compound of formula II

h) optionally hydrolyzing a compound of formula II

 to form a compound of formula I; and

i) optionally salifying a compound of formula I.

The synthesis methodology for making the 1H-indole-3-glyoxylamide sPLA₂inhibitor starting material may be by any suitable means available toone skilled in the chemical arts. However, such methodology is not partof the present invention which is a method of use, specifically, amethod of treating mammal afflicted or susceptible to non-rheumatoidarthritis.

The method of the invention is for treatment of a mammal, including ahuman, afflicted with a non-rheumatoid arthritis, said method comprisingadministering to said human a therapeutically effective amount of thecompound represented by formula (Ia), or a pharmaceutically acceptablesalt or prodrug derivative thereof;

wherein;

both X are oxygen;

R₁ is selected from the group consisting of

 where R₁₀ is a radical independently selected from halo, C₁-C₁₀ alkyl,C₁-C₁₀ alkoxy, —S—(C₁-C₁₀ alkyl), and C₁-C₁₀ haloalkyl and t is a numberfrom 0 to 5;

R₂ is selected from the group; halo, cyclopropyl, methyl, ethyl, andpropyl;

R₄ and R₅ are independently selected from hydrogen, a non-interferingsubstituent, or the group, —(L_(a))-(acidic group); wherein —(L_(a))— isan acid linker; provided, the acid linker group, —(L_(a))—, for R₄ isselected from the group consisting of;

 and provided, the acid linker, —(L_(a))—, for R₅ is selected from groupconsisting of;

 wherein R₈₄ and R₈₅ are each independently selected from hydrogen,C₁-C₁₀ alkyl, aryl, C₁-C₁₀ alkaryl, C₁-C₁₀ aralkyl, carboxy, carbalkoxy,and halo; and

provided, that at least one of R₄ and R₅ must be the group,—(L_(a))-(acidic group) and wherein the (acidic group) on the group—(L_(a))-(acidic group) of R₄ or R₅ is selected from —CO₂H, —SO₃H, or—P(O)(OH)₂;

R₆ and R₇ are each independently selected form hydrogen andnon-interfering substituents, with the non-interfering substituentsbeing selected from the group consisting of the following: C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₇-C₁₂ aralkyl, C₇-C₁₂ alkaryl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl,C₁-C₆ alkoxy, C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₁₂ alkoxyalkyl,C₂-C₁₂ alkoxyalkyloxy, C₂-C₁₂ alkylcarbonyl, C₂-C₁₂ alkylcarbonylamino,C₂-C₁₂ alkoxyamino, C₂-C₁₂ alkoxyaminocarbonyl, C₂-C₁₂ alkylamino, C₁-C₆alkylthio, C₂-C₁₂ alkylthiocarbonyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₂-C₆ haloalkoxy, C₁-C₆ haloalkylsulfonyl, C₂-C₆haloalkyl, C₁-C₆ hydroxyalkyl, —C(O)O(C₁-C₆ alkyl), —(CH₂)_(n)—O—(C₁-C₆alkyl), benzyloxy, phenoxy, phenylthio, —(CONHSO₂R), —CHO, amino,amidino, bromo, carbamyl, carboxyl, carbalkoxy, —(CH₂)_(n)—CO₂H, chloro,cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino,hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO₃H,thioacetal, thiocarbonyl, and C₁-C₆ carbonyl; where n is from 1 to 8.

Preferred for practicing the method of the invention are1H-indole-3-glyoxylamide compounds and all correspondingpharmaceutically acceptable salts, solvates and prodrug derivativesthereof which are useful in the method of the invention include thefollowing:

(A)[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid,

(B)dl-2-[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]propanoicacid,

(C)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]aceticacid,

(D)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-3-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]aceticacid,

(E)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-4-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]aceticacid,

(F)[[3-(2-Amino-1,2-dioxoethyl)-1-[(2,6-dichlorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]aceticacid

(G)[[3-(2-Amino-1,2-dioxoethyl)-1-[4(-fluorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]aceticacid,

(H)[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-[(1-naphthalenyl)methyl]-1H-indol-4-yl]oxy]aceticacid,

(I)[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid,

(J)[[3-(2-Amino-1,2-dioxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-4-yl]oxy]aceticacid,

(K)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-ethyl-1H-indol-4-yl]oxy]aceticacid,

(L)[[3-(2-amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]aceticacid,

(M)[[3-(2-Amino-1,2-dioxoethyl)-2-cyclopropyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid,

(N)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-cyclopropyl-1H-indol-4-yl]oxy]aceticacid,

(O)4-[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoicacid,

(P) mixtures of (A) through (P) in any combination.

Particularly useful prodrugs of the compounds of formula (I) and namedcompounds (A) thru (O) are the simple aromatic and aliphatic esters,such as the methyl ester, ethyl ester, n-propyl ester, isopropyl ester,n-butyl ester, sec-butyl, tert-butyl ester, N,N-diethylglycolamidoester, and morpholino-N-ethyl ester. Methods of making ester prodrugsare disclosed in U.S. Pat. No. 5,654,326. Additional methods of prodrugsynthesis are disclosed in U.S. Provisional Patent Application SerialNo. 60/063280 filed Oct. 27, 1997 (titled, N,N-diethylglycolamido esterProdrugs of Indole sPLA2 Inhibitors), the entire disclosure of which isincorporated herein by reference; U.S. Provisional Patent ApplicationSerial No. 60/063646 filed Oct. 27, 1997 (titled, Morpholino-N-ethylEster Prodrugs of Indole sPLA2 Inhibitors), the entire disclosure ofwhich is incorporated herein by reference; and U.S. Provisional PatentApplication Serial No. 60/063284 filed Oct. 27, 1997 (titled, IsopropylEster Prodrugs of Indole sPLA₂ Inhibitors), the entire disclosure ofwhich is incorporated herein by reference.

Most preferred in the practice of the method of the invention are theacid, sodium salt, methyl ester, and morpholino-N-ethyl ester forms of[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4yl]oxy]aceticacid as represented by the following formulae:

Synthesis methods for 1H-indole-3-glyoxylamide sPLA₂ inhibitors areadditionally depicted in the following reaction scheme:

1H-indole-3-glyoxylamide Reaction Scheme

Explanation of Reaction Scheme

To obtain the glyoxylamides substituted in the 4-position with an acidicfunction through an oxygen atom, the reactions outlined in scheme 1 areused (for conversions 1 through 5, see ref. Robin D. Clark, Joseph M.Muchowski, Lawrence E. Fisher, Lee A. Flippin, David B. Repke, MichelSouchet, Synthesis, 1991, 871-878, the disclosures of which areincorporated herein by reference). The ortho-nitrotoluene, 1, is readilyreduced to the 2-methylaniline, 2, using Pd/C as catalyst. The reductioncan be carried out in ethanol or tetrahydrofuran (THF) or a combinationof both, using a low pressure of hydrogen. The aniline, 2, on heatingwith di-tert-butyl dicarbonate in THF at reflux temperature is convertedto the N-tert-butylcarbonyl derivative, 3, in good yield. The dilithiumsalt of the dianion of 3 is generated at −40 to −20° C. in THF usingsec-butyl lithium and reacted with the appropriately substitutedN-methoxy-N-methylalkanamide. This product, 4, may be purified bycrystallization from hexane, or reacted directly with trifluoroaceticacid in methylene chloride to give the 1,3-unsubstituted indole 5. The1,3-unsubstituted indole 5 is reacted with sodium hydride indimethylformamide at room temperature (20-25° C.) for 0.5-1.0 hour. Theresulting sodium salt of 5 is treated with an equivalent of arylmethylhalide and the mixture stirred at a temperature range of 0-100° C.,usually at ambient room temperature, for a period of 4 to 36 hours togive the 1-arylmethylindole, 6. This indole, 6, is O-demethylated bystirring with boron tribromide in methylene chloride for approximately 5hours (see ref. Tsung-Ying Shem and Charles A Winter, Adv. Drug Res.,1977, 12, 176, the disclosure of which is incorporated herein byreference). The 4-hydroxyindole, 7, is alkylated with an alphabromoalkanoic acid ester in dimethylformamide (DMF) using sodium hydrideas a base, with reactions conditions similar to that described for theconversion of 5 to 6. The a-[(indol-4-yl)oxy]alkanoic acid ester, 8, isreacted with oxalyl chloride in methylene chloride to give 9, which isnot purified but reacted directly with ammonia to give the glyoxamide10. This product is hydrolyzed using 1N sodium hydroxide in MeOH. Thefinal glyoxylamide, 11, is isolated either as the free carboxylic acidor as its sodium salt or in both forms.

The most preferred compound,[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4yl]oxy]aceticacid (as well as its sodium salt and methyl ester) useful in thepractice of the method of the invention, may be prepared by thefollowing procedure:

Preparation of[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid, a compound represented by the formula:

Part A. Preparation of 2-Ethyl-4-methoxy-1H-indole

A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexaneis added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3g, 0.09 mol) in 250 mL of THF keeping the temperature below −40° C. witha dry ice-ethanol bath. The bath is removed and the temperature allowedto rise to 0° C. and then the bath replaced. After the temperature hascooled to −60° C., 18.5 g (0.18 mol) of N-methoxy-N-methylpropanamide inan equal volume of THF iss added dropwise. The reaction mixture isstirred 5 minutes, the cooling bath removed and stirred an additional 18hours. It is then poured into a mixture of 300 mL of ether and 400 mL of0.5N HCl. The organic layer is separated, washing with water, brine,dried over MgSO₄, and concentrated at reduced pressure to give 25.5 g ofa crude of 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone.This material is dissolved in 250 mL of methylene chloride and 50 mL oftrifluoroacetic acid and stirred for a total of 17 hours. The mixture isconcentrated at reduced pressure and ethyl acetate and water added tothe remaining oil. The ethyl acetate is separated, washed with brine,dried (MgSO₄) and concentrated. The residue is chromatographed threetimes on silica eluting with 20% EtOAc/hexane to give 13.9 g of2-ethyl-4-methoxy-1H-indole.

Analysis for C₁₁H₁₃NO: Calculated: C, 75.40; H, 7.48; N, 7.99; Found: C,74.41; H, 7.64; N, 7.97.

Part B. Preparation of 2-Ethyl-4-methoxy-1-(phenylmethyl)-1H-indole

2-Ethyl-4-methoxy-1H-indole (4.2 g, 24 mmol) is dissolved in 30 mL ofDMF and 960 mg (24 mmol) of 60% NaH/mineral oil is added. After 1.5hours, 2.9 mL (24 mmol) of benzyl bromide is added. After 4 hours, themixture is diluted with water extracting twice with ethyl acetate. Thecombined ethyl acetate is washed with brine, dried (MgSO₄) andconcentrated at reduced pressure. The residue is chromatographed onsilica gel and eluted with 20% EtOAc/hexane to give 3.1 g (49% yield) of2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole.

Part C. Preparation of 2-Ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole

A solution of 3.1 g (11.7 mmol) of2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole and 48.6 mL of 1MBBr₃/CH₂Cl₂ in 50 mL of methylene chloride is stirred at roomtemperature for 5 hours and concentrated at reduced pressure. Theresidue is dissolved in ethyl acetate, washed with brine and dried(MgSO₄). After concentrating at reduced pressure, the residue ischromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.58g (54% yield) of 2-ethyl-4-hydroxy-1(phenylmethyl)-1H-indole, mp, 86-90°C.

Analysis for C₁₇H₁₇NO: Calculated: C, 81.24; H, 6.82; N, 5.57 Found: C,81.08; H, 6.92; N, 5.41.

Part D. Preparation of[[2-Ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic Acid tert-butylEster

2-Ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole (5.82 g, 20 mmol) is addedto 7.82 g (24 mmol) cesium carbonate in 25 mL DMF and the mixture isstirred at 35° C. for 30 minutes. After cooling to 20° C., a solution oftert-butyl bromoacetate (4.65 g, 23.8 mmol) in 5 mL DMF is added andstirring maintained until the reaction is judged complete by TLCanalysis (several hours). The mixture is diluted with water andextracted with ethyl acetate. The ethyl acetate solution is washed withbrine, dried (MgSO₄) and concentrated at reduced pressure to give 6.8 gof solid.

Mass spectrum: 365

Analyses for C₂₃H₂₇NO₃: Calculated: C, 75.59; H, 7.75; N, 3.83; Found:C, 75.87; H, 7.48; N, 3.94.

Part E. Preparation of[[2-Ethyl-1-(phenylmethyl)-3-ureido-1H-indol-4-yl)oxy]acetic Acidtert-butyl Ester

A solution of 2.3 g (6.3 mmol)[[2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid tert-butylester and 4.8 g (12.6 mmol) bis(2,2,2-trichloroethyl)azodicarboxylate indiethyl ether is stirred for 24 hours at room temperature. The resultingsolid is filtered and vacuum dried. This adduct (1 g, 1.3 mmol) isdissolved in 10 mL of THF and treated with zinc (1 g) and glacial aceticacid (0.5 mL). After stirring for 30 minutes at room temperature anexcess of trimethylsilylisocyanate in 1 mL of THF is added and stirringis continued at room temperature for 18 hours. The mixture is dilutedwith water and extracted with ethyl acetate. The organic layer is washedwith brine, dried over MgSO₄ and concentrated to dryness to give 0.385 g(69% yield) of the subtitled material. Mass spectrum: 423.

Analyses for C₂₄H₂₉N₃O₄: Calculated: C, 68.07; H, 6.90; N, 9.92; Found:C, 67.92; H, 6.84; N, 9.70.

Part F. Preparation of[[3-(2-Amino-1,2-dioxoethyl)-2ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticAcid

A mixture of 788 mg (2 mmol) of[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4yl]oxy]aceticacid methyl ester, 10 mL of 1n NaOH and 30 mL of MeOH is heated tomaintain reflux for 0.5 hour, stirred at room temperature for 0.5 hourand concentrated at reduced pressure. The residue is taken up in ethylacetate and water, the aqueous layer separated and made acidic to pH 2-3with 1N HC1. The precipitate is filtered and washed with ethyl acetateto give 559 mg (74% yield) of[[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4yl]oxy]aceticacid, mp, 230-234° C.

Analyses for C₂₁H₂₀N₂O₅: Calculated: C, 65.96; H, 5.80; N, 7.33; Found:C, 66.95; H, 5.55; N, 6.99.

b) 1H-indole-3-hydrazide sPLA₂ inhibitors useful in practicing themethod of the invention are described in U.S. Pat. No. 5,578,634; theentire disclosure of which is incorporated herein by reference. Themethod of the invention is for treatment of a mammal, including a human,afflicted with a non-rheumatoid arthritis, said method comprisingadministering to said human a therapeutically effective amount of thedescribed as 1H-indole-3-acetic acid hydrazides represented by theformula (Ib), and pharmaceutically acceptable salts, and prodrugsthereof;

 wherein;

X is oxygen or sulfur;

R₁ is selected from groups (i), (ii) and (iii) where;

(i) is C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, C₄-C₂₀ alkynyl, C₄-C₂₀ haloalkyl,C₄-C₁₂ cycloalkyl, or

(ii) is aryl or aryl substituted by halo, —CN, —CHO, —OH, —SH, C₁-C₁₀alkylthio, C₁-C₁₀ alkoxy, C₁-C₁₀ alkyl, carboxyl, amino, orhydroxyamino;

(iii) is

 where y is from 1 to 8, R₇₄ is, independently, hydrogen or C₁-C₁₀alkyl, and R₇₅ is aryl or aryl substituted by halo, —CN, —CHO, —OH,nitro, phenyl, —SH, C₁-C₁₀ alkylthio, C₁-C₁₀ alkoxy, C₁-C₁₀ alkyl,amino, hydroxyamino or a substituted or unsubstituted 5 to 8 memberedheterocyclic ring;

R₂ is halo, C₁-C₃ alkyl, ethenyl, C₁-C₂ alkylthio, C₁-C₂ alkoxy, —CHO,—CN;

each R₃ is independently hydrogen, C₁-C₃ alkyl, or halo;

R₄, R₅, R₆, and R₇ are each independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀alkenyl, C₁-C₁₀ alkynyl, C₃-C₈ cycloalkyl, aryl, aralkyl, or any twoadjacent hydrocarbyl groups in the set R₄, R₅, R₆, and R₇ combined withthe ring carbon atoms to which they are attached to form a 5 or 6membered substituted or unsubstituted carbocyclic ring; or C₁-C₁₀haloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy, C₄-C₈ cycloalkoxy, phenoxy,halo, hydroxy, carboxyl, —SH, —CN, —S(C₁-C₁₀ alkyl), arylthio,thioacetal, —C(O)O(C₁-C₁₀ alkyl), hydrazino, hydrazido, —NH₂, —NO₂,—NR₈₂R₈₃, and —C(O)NR₈₂R₈₃, where, R₈₂ and R₈₃ are independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ hydroxyalkyl, or taken together with N,R₈₂ and R₈₃ form a 5 to 8 membered heterocyclic ring; or a group havingthe formula;

 where,

each R₇₆ is independently selected from hydrogen, C₁-C₁₀ alkyl, hydroxy,or both R₇₆ taken together are ═O;

p is 1 to 8,

Z is a bond, —O—, —N(C₁-C₁₀ alkyl)—, —NH, or —S—; and

Q is —CON(R₈₂R₈₃), -5-tetrazolyl, —SO₃H,

 where R₈₆ is independently selected from hydrogen, a metal, or C₁-C₁₀alkyl.

The synthesis of the 1H-indole-3-acetic acid hydrazides of structure (I)can be accomplished by known methods such as outlined in the followingreaction schemes:

The 1H-indole-3-acetic acid ester can be readily alkylated by an alkylhalide or arylalkyl halide in a solvent such as N,N-dimethylformamide(DMF) in the presence of a base (meth a) to give the intermediate1-alkyl-1H-indole-3-acetic acid esters, III. Bases such as potassiumt-butoxide and sodium hydride were particularity useful. It isadvantageous to react the indole, II, with the base to first form thesalt of II and then add the alkylating agent. Most alkylations can becarried out at room temperature. Treatment of the1-alkyl-1H-indole-3-acetic acid esters, III, with hydrazine or hydrazinehydrate in ethanol(meth b) gives the desired 1-alkyl-1H-indole-3-aceticacid hydrazides, I. This condensation to form I is usually carried outat the reflux temperature of the solvent for a period of 1 to 24 hours.

c) 1H-indole-3-acetamide sPLA₂ inhibitors and methods of making theseinhibitors are set out in U.S. Pat. No. 5,684,034, the entire disclosureof which is incorporated herein by reference. The method of theinvention is for treatment of a mammal, including a human, afflictedwith a non-rheumatoid arthritis, said method comprising administering tosaid human a therapeutically effective amount of the compoundrepresented by (IIb), and pharmaceutically acceptable salts and prodrugderivatives thereof,

 wherein

X is oxygen or sulfur;

R₁₁ is selected from groups (i), (ii) (iii) and (iv) where;

(i) is C₆-C₂₀ alkyl, C₆-C₂₀ alkenyl, C₆-C₂₀ alkynyl, C₆-C₂₀ haloalkyl,C₄-C₁₂ cycloalkyl, or

(ii) is aryl or aryl substituted by halo, nitro, —CN, —CHO, —OH, —SH,C₁-C₁₀ alkyl, C₁-C₁₀ alkylthio, C₁-C₁₀ alkoxyl, carboxyl, amino, orhydroxyamino; or

(iii) is —(CH₂)_(n)—(R₈₀), or —(NH)—(R₈₁), where n is 1 to 8, and R₈₀ isa group recited in (i), and R₈₁ is selected from a group recited in (i)or (ii);

(iv) is

 where R₈₇ is hydrogen or C₁-C₁₀ alkyl, and R₈₈ is selected from thegroup; phenyl, naphthyl, indenyl, and biphenyl, unsubstituted orsubstituted by halo, —CN, —CHO, —OH, —SH, C₁-C₁₀ alkylthio, C₁-C₁₀alkoxyl, phenyl, nitro, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, carboxyl, amino,hydroxyamino; or a substituted or unsubstituted 5 to 8 memberedheterocyclic ring;

R₁₂ is halo, C₁-C₂ alkylthio, or C₁-C₂ alkoxy;

each R₁₃ is independently hydrogen, halo, or methyl;

R₁₄, R₁₅, R₁₆, and R₁₇ are each independently hydrogen, C₁-C₁₀ alkyl,C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl, C₃-C₈ cycloalkyl, aryl, aralkyl, or anytwo adjacent hydrocarbyl groups in the set R₁₄, R₁₅, R₁₆, and R₁₇,combine with the ring carbon atoms to which they are attached to form a5 or 6 membered substituted or unsubstituted carbocyclic ring; or C₁-C₁₀haloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy, C₄-C₈ cycloalkoxy, phenoxy,halo, hydroxy, carboxyl, —SH, —CN, C₁-C₁₀ alkylthio, arylthio,thioacetal, —C(O)O(C₁-C₁₀ alkyl), hydrazide, hydrazino, hydrazido, —NH₂,—NO₂, —NR₈₂R₈₃, and —C(O)NR₈₂R₈₃, where, R₈₂ and R₈₃ are independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ hydroxyalkyl, or taken together with N,R₈₂ and R₈₃ form a 5 to 8 membered heterocyclic ring; or

a group having the formula;

 where,

R₈₄ and R₈₅ are each independently selected from hydrogen, C₁-C₁₀ alkyl,hydroxy, or R₈₄ and R₈₅ taken together are ═O;

p is 1 to 5,

Z is a bond, —O—, —N(C₁-C₁₀ alkyl)—, —NH—, or —S—; and

Q is —CON(R₈₂R₈₃), -5-tetrazolyl, —SO₃H,

 where n is 1 to 8, R₈₆ is independently selected from hydrogen, ametal, or C₁-C₁₀ alkyl, and R₉₉ is selected from hydrogen or C₁-C₁₀alkyl.

The synthesis of the 1H-indole-3-acetamides of structure (IIb) useful inthe method of the invention can be accomplished by known methods. Aprocedure useful for the syntheses of these compounds is shown in thefollowing reaction scheme:

The 1H-indole-3-acetamide II may be alkylated by an alkyl halide orarylalkyl halide in a solvent such as N,N-dimethylformamide (DMF) in thepresence of a base (method a) to give intermediate1-alkyl-1H-indole-3-acetic acid esters, III. Bases such as potassiumt-butoxide and sodium hydride are useful. It is advantageous to reactthe indole, II, with the base to first form the salt of II and then addalkylating agent. Treatment of the 1-alkyl-1H-indole-3-acetic acidesters, III, with hydrazine or hydrazine hydrate in ethanol (method b)gives the desired 1-alkyl-1H-indole-3-acetic acid hydrazides, IV. Thiscondensation to form IV may be carried out at the reflux temperature ofthe solvent for a period of 1 to 24 hours. The acetic acid hydrazides,IV, are hydrogenated to give the acetamides, I, by heating with Raneynickel in ethanol (method c). The intermediate acetic acid esters, III,can be first hydrolyzed to the acetic acid derivatives, V (method d),which on treatment with an alkyl chloroformate followed by anhydrousammonia, also give amides, I (method e).

d) 1H-indole-1-functional sPLA₂ inhibitors of the hydrazide, amide, orglyolxylamide types as described in U.S. Pat. No. 5,641,800, the entiredisclosure of which is incorporated herein by reference. The method ofthe invention is for treatment of a mammal, including a human, afflictedwith a non-rheumatoid arthritis, said method comprising administering tosaid human a therapeutically effective amount of a 1H-indole-1-acetamideor a pharmaceutically acceptable salt, solvate or prodrug derivativethereof; wherein said compound is represented by the formula (Ic);

 wherein for Formula (Ic);

X is oxygen or sulfur;

each R₁ is independently hydrogen, or C₁-C₃ alkyl;

R₃ is selected from groups (a), (b) and (c) where;

(a) is C₇-C₂₀ alkyl, C₇-C₂₀ alkenyl, C₇-C₂₀ alkynyl, carbocyclicradical, or heterocyclic radical, or

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents; or

(c) is the group —(L)—R₈₀; where, —(L)— is a divalent linking group of 1to 12 atoms and where R₈₀ is a group selected from (a) or (b);

R₂ is hydrogen, halo, C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl,—O—(C₁-C₂ alkyl), —S—(C₁-C₂ alkyl), or a non-interfering substituenthaving a total of 1 to 3 atoms other than hydrogen;

R₆ and R₇ are independently selected from hydrogen, a non-interferingsubstituent, or the group, —(L_(a))—(acidic group); wherein —(L_(a))—,is an acid linker having an acid linker length of 1 to 10; provided,that at least one of R₆ and R₇ must be the group, —(L_(a))—(acidicgroup);

R₄ and R₅ are each independently selected from hydrogen, non-interferingsubstituent, carbocyclic radical, carbocyclic radical substituted withnon-interfering substituents, heterocyclic radical, and heterocyclicradical substituted with non-interfering substituents.

1H-indole-1-hydrazide compounds useful as sPLA₂ inhibitors in thepractice of the method of the invention are as follows:

A 1H-indole-1-hydrazide compound or a pharmaceutically acceptable salt,solvate or prodrug derivative thereof; wherein said compound isrepresented by the formula (IIc);

 wherein for formula (IIc);

X is oxygen or sulfur;

each R₁ is independently hydrogen, or C₁-C₃ alkyl;

R₃ is selected from groups (a), (b) and (c) where;

(a) is C₇-C₂₀ alkyl, C₇-C₂₀alkenyl, C₇-C₂₀ alkynyl, carbocyclic radical,or heterocyclic radical, or

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituent; or

(c) is the group —(L)—R₈₀; where, —(L)— is a divalent linking group of 1to 12 atoms and where R₈₀ is a group selected from (a) or (b);

R₂ is hydrogen, halo, C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl,—O—(C₁-C₂ alkyl), —S—(C₁-C₂ alkyl), or a non-interfering substituenthaving a total of 1 to 3 atoms other than hydrogen;

R₆ and R₇ are independently selected from hydrogen, a non-interferingsubstituent, or the group, —(L_(a))—(acidic group); wherein —(L_(a))—,is an acid linker having an acid linker length of 1 to 10; provided,that at least one of R₆ and R₇ must be the group, —(L_(a))—(acidicgroup);

R₄ and R₅ are each independently selected from hydrogen, non-interferingsubstituent, carbocyclic radical, carbocyclic radical substituted withnon-interfering substituents, heterocyclic radical, and heterocyclicradical substituted with non-interfering substituents.

e) Indolizine sPLA₂ inhibitors and their method of preparation aredescribed in U.S. patent application Ser. No. 08/765566, filed Jul. 20,1995 (titled, “Synovial Phospholipase A2 Inhibitor Compounds Having anIndolizine Type Nucleus, Parmaceutical Formulations Containing Saidcompounds, and Therapeutic Methods of Using said Compounds”), the entiredisclosure of which is incorporated herein by reference; and also inEuropean Patent Publication No. 0772596, published May 14, 1997. Themethod of the invention is for treatment of a mammal, including a human,afflicted with a non-rheumatoid arthritis, said method comprisingadministering to said human a therapeutically effective amount of1H-indole-1-functional compound or a pharmaceutically acceptable salt,solvate or prodrug derivative thereof; wherein said compound isrepresented by the formula (Id);

 wherein;

X is oxygen or sulfur;

each R₁₁ is independently hydrogen, C₁-C₃ alkyl, or halo;

R₁₃ is selected from groups (a), (b) and (c) where;

(a) is C₇-C₂₀ alkyl, C₇-C₂₀ alkenyl, C₇-C₂₀ alkynyl, carbocyclicradical, or heterocyclic radical, or

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents; or

(c) is the group —(L)—R₈₀; where, —(L)— is a divalent linking group of 1to 12 atoms and where R₈₀ is a group selected from (a) or (b);

R₁₂ is hydrogen, halo, C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄cycloalkenyl, —O—(C₁-C₂ alkyl), —S—(C₁-C₂ alkyl), or a non-interferingsubstituent having a total of 1 to 3 atoms other than hydrogen;

R₁₇ and R₁₈ are independently selected from hydrogen, a non-interferingsubstituent, or the group, —(L_(a))-(acidic group); wherein —(L_(a))—,is an acid linker having an acid linker length of 1 to 10; provided,that at least one of R₁₇ and R₁₈ must be the group, —(L_(a))-(acidicgroup); and

R₁₅ and R₁₆ are each independently selected from hydrogen,non-interfering substituent, carbocyclic radical, carbocyclic radicalsubstituted with non-interfering substituents, heterocyclic radical, andheterocyclic radical substituted with non-interfering substituents.

Particularly preferred 1H-indole-1-functional compounds useful as sPLA₂inhibitors in the practice of the method of the invention are asfollows:

An indolizine-1-acetic acid hydrazide compound or a pharmaceuticallyacceptable salt, solvate or prodrug derivative thereof where saidcompound is represented by the formula (IId);

Particularly preferred 1H-indole-1-functional compounds useful as sPLA₂inhibitors in the practice of the method of the invention are asfollows:

An indolizine-1-glyoxylamide compound or a pharmaceutically acceptablesalt, solvate or prodrug derivative thereof; wherein said compound isrepresented by the formula (IIId);

Another preferred 1H-indole-1-functional compounds useful as sPLA₂inhibitors in the practice of the method of the invention are asfollows:

An indolizine-3-acetamide compound or a pharmaceutically acceptablesalt, solvate or prodrug derivative thereof; wherein said compound isrepresented by the formula (IVd), as set out below:

 wherein;

X is selected from oxygen or sulfur;

each R₃ is independently hydrogen, C₁-C₃ alkyl, or halo;

R₁ is selected from groups (a), (b) and (c) where;

(a) is C₇-C₂₀ alkyl, C₇-C₂₀ alkenyl, C₇-C₂₀ alkynyl, carbocyclicradical, or heterocyclic radical, or

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents; or

(c) is the group —(L)—R₈₀; where, —(L)— is a divalent linking group of 1to 12 atoms and where R₈₀ is a group selected from (a) or (b);

R₂ is hydrogen, halo, C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl,—O—(C₁-C₂ alkyl), —S—(C₁-C₂ alkyl), or a non-interfering substituenthaving a total of 1 to 3 atoms other than hydrogen;

R₅ and R₆ are independently selected from hydrogen, a non-interferingsubstituent, or the group, —(L_(a))-(acidic group); wherein —(L_(a))—,is an acid linker having an acid linker length of 1 to 10; provided,that at least one of R₅ and R₆ must be the group, —(L_(a))-(acidicgroup);

R₇ and R₈ are each independently selected from hydrogen, non-interferingsubstituent, carbocyclic radical, carbocyclic radical substituted withnon-interfering substituents, heterocyclic radical, and heterocyclicradical substituted with non-interfering substituents.

Particularly preferred 1H-indole-1-functional compounds useful as sPLA₂inhibitors in the practice of the method of the invention are asfollows:

An indolizine-3-hydrazide compound or a pharmaceutically acceptablesalt, solvate or prodrug derivative thereof; wherein said compound isrepresented by the formula (Vd), as set out below:

Particularly preferred 1H-indole-1-functional compounds useful as sPLA₂inhibitors in the practice of the method of the invention are asfollows:

An indolizine-3-glyoxylamide compound or a pharmaceutically acceptablesalt, solvate or prodrug derivative thereof; wherein said compound isrepresented by the formula (VId), as set out below:

Particularly preferred 1H-indole-1-functional compounds useful as sPLA₂inhibitors in the practice of the method of the invention are asfollows:

An indolizine-1-acetamide functional compound or a pharmaceuticallyacceptable salt, solvate or prodrug derivative thereof; wherein saidcompound is selected from the group represented by the followingformulae:

 and mixtures of the above compounds.

Other particularly preferred 1H-indole-1-functional compounds useful assPLA₂ inhibitors in the practice of the method of the invention are asfollows:

An indolizine-1-glyoxylamide functional compound and a pharmaceuticallyacceptable salt, solvate or prodrug derivative thereof; wherein saidcompound is selected from the group represented by the followingformulae:

 and mixtures of the above compounds.

The indolizine compounds may be made by one of more of the followingreaction schemes:

The following abbreviations are used throughout the synthesis Schemes:

Bn benzyl

THF tetrahydrofuran

LAH lithium aluminum hydride

LDA lithium diiopropyl amine

DBU 1,8-diazabicyclo 5.4.0]undec-7-une

The anion of 2-methyl-5-methoxypyridine is formed in THF using lithiumdiisopropyl amide and reacted with benzonitrile to produce 2. Alkylationof the nitrogen of 2 by 1-bromo-2-butanone followed by base catalyzedcyclization forms 3 which is reduced by LAH to 4. Sequential treatmentof 4 with oxalyl chloride and ammonia gives 8. Alternatively, 4 isacylated with ethyl oxalyl chloride to give 5 which is converted to 6with lithium hydroxide and then to 8 by sequential treatment with ethylchloroformate and ammonium hydroxide. Demethylation of 8 by BBr₃ yields9 which is O-alkylated using base and ethyl 4-bromobutyrate to form 10.Hydrolysis of 10 by aqueous base produces 11.

Scheme 2 - Part 1

17 R₁ R₂ R₃ a: OEt Et Bn b: NH₂ Et Bn c: NH₂ Et CH₂COEt d: NH₂ cyclo-PrBn 18 R₁ R₂ R₃ R₄ a: OEt Et Bn o-Ph—Ph b: NH₂ Et Bn o-Ph—Ph c: NH₂ Et Bnm-Cl—Ph d: NH₂ Et CH₂COEt m-Cl—Ph e: NH₂ cyclo-Pr Bn o-Ph—Ph f: NH₂ EtBn Ph g: NH₂ Et Bn 1-Naphthyl

Compound 12 (N. Desidiri, A. Galli, I. Sestili, and M. L. Stein, Arch.Pharm. (Weinheim) 325, 29, (1992)) is reduced by hydrogen in thepresence of Pd/C to 14 which gives 15 on ammonolysis using ammoniumhydroxide. O-alkylation of 15 using benzyl chloride and base affords 16.Alkylation of the nitrogen atom of 13 or 16 by 1-bromo-2-ketonesfollowed by base catalyzed cyclization yields indolizines 17 which areacylated by aroyl halides to form 18.

Scheme 2 - Part 2

19 R₁ R₂ R₃ R₄ a: CH₂OH Et Bn o-Ph—Ph b: CONH₂ Et Bn o-Ph—Ph c: CONH₂ EtCH₂CH(OH)Et m-Cl—Ph d: CONH₂ Et Bn m-Cl—Ph e: CONH₂ cyclo-Pr Bn o-Ph—Phf: CONH₂ Et Bn Ph g: CONH₂ Et Bn 1-Naphthyl 20-22 R₂ R₃ R₄ v: Et Et Phw: Et Me 1-Naphthyl x: Et Bn o-Ph—Ph y: Et Bn m-Cl—Ph z: cyclo-Pr Meo-Ph—Ph

Reduction of 18 by tert-butylamine-borohydride and aluminum chlorideyields 19 which is reduced by hydrogen in the presence of Pd/C to give20. O-alkylation of 20 by benzyl bromoacetate and base forms 21 which isconverted to the acid 22 by debenzylation using hydrogen in the presenceof Pd/C.

Scheme 3 - Part 1

26-28 R₁ R₂ a: Et Ph b: Et o-Ph—Ph c: Et m-Cl—Ph d: Et m-CF₃—Ph e: Et1-Naphthyl f: cyclo-Pr o-Ph—Ph

Compound 23 (N. Desideri F. Manna, M. L. Stein, G. Bile, W. Filippeelli,and E. Marmo, Eur. J. Med. Chem. Chim. Ther., 18, 295, (1983)) isO-alkylated using sodium hydride and benzyl chloride to give 24.N-alkylation of 24 by 1-bromo-2-butanone or chloromethylcyclopropylketone and subsequent base catalyzed cyclization gives 25 which isacylated by aroyl halide to give 26. Hydrolysis of the ester function of26 followed by acidification forms an acid which is thermallydecarboxylated to give 27. Reduction of the ketone function of 27 by LAHyields indolizines 28.

Heating a mixture of 3-bromo-4-phenyl-butan-2-one or3-bromo-4-cyclohexyl-butan-2-one and ethyl pyridine-2-acetate, or asubstituted derivative, in the presence of base yields indolizine 31.Treatment of 31 with aqueous base in DMSO at elevated temperaturefollowed by acidification gives 32 which is thermally decarboxylated to33.

Scheme 4 - Part 1

35-40 R₁ R₂ R₃ R₄ a: H H Et Ph b: H Me Et Ph c: Me Me Et Ph d: H H Eto-Ph—Ph e: H Me Et o-Ph—Ph f: Me Me Et o-Ph—Ph g: H H Me Ph h: H H Etm-Cl—Ph i: H H Et m-CF₃—Ph j: H H Et 1-Naphthyl k: H H cyclo-Pr o-Ph—Phl: H H Me cyclo-Hex

Sequential treatment of 28 or 33 with oxalyl chloride and ammoniumhydroxide forms 35 which is debenzylated by hydrogen in the presence ofPd/C to give 36. Indolizines 36 are O-alkylated using sodium hydride andbromoacetic acid esters to form 37, 38, or 39 which are converted toindolizines 40 by hydrolysis with aqueous base followed byacidification.

The O-alkylation of 36h produces nitrite 41 which is converted to 42 onreaction with trialkyltin azide.

Scheme 5

45, 46 R₁ R₂ a: Bn Et b: Me Et c: Bn Me d: Me cyclo-Pro e: Bn cyclo-Pro47-52 R₁ R₂ R₃ a-o Bn Et a-o (see below) p Bn Me 1-adamantyl q Bn Meo-biphenyl r Bn cycloPro phenyl s Me Et p-n-C₄H₉—Ph t Bn Me cyclo-Hex uMe cycloPro cyclo-Hex v Bn cycloPro cyclopentyl w Bn Me cyclolpentyl

47-52  R₃ = a:

b:

c:

d:

e: n-C₄H₉ f:

g:

h:

i:

j:

k:

l:

m:

n:

o:

The hydroxypyridine is O-alkylated to give 44 which is heated with2-haloketones to produce 45. Treatment of 45 with base causescyclization to 46 which on heating with acid chlorides yieldsacylindolizines 47 which are reduced by aluminum hydride to thecorresponding alkylindolizines 48. Sequential treatment of 48 withoxalyl chloride and then ammonia gives 49. Cleavage of the etherfunctionality of 49 yields 50. The oxyacetic ester derivatives 51 areformed by O-alkylation of 50 and then hydrolyzed to the oxyacetic acids52.

Scheme 6 - Part 1

54, 55 R₁ R₂ a: Me o-biphenyl b: Et o-biphenyl c: iPro o-biphenyl d:cyclo-Pro cyclohexyl e: tBu o-biphenyl f: cyclopentyl o-biphenyl

56-58 R₁ R₂ R₁ R₂ a Me o-biphenyl f cyclopentyl o-biphenyl b Eto-biphenyl g Et m-biphenyl c iPr o-biphenyl h Et cinnamyl d cycloProo-biphenyl i Et phenethyl e tBu o-biphenyl j cyclopropyl 1-naphthyl kcyclopropyl cyclohexyl

59a-k  R = a: —ONa b: —OCH(Me)OCOOMe c: —OCH(Me)OCOOiPr d: —OCH₂OCOtBue:

f:

g:

h:

i:

j: —(CH₂)₂O— (dimer) k: COEt

Pyridine 43 is O-alkylated to produce 53. Heating 53 with 2-haloketonesgives intermediate N-alkylated pyridinium compounds which are cyclizedto 54 on treatment with base. Heating 54 with acyl chlorides gives theacylindolizines 55 which are reduced to the alkylindolizines 56 bysodium borohydride-aluminum chloride. Alternatively, 56 are produced byC-alkylation of 54 using alkyl halides. Sequential treatment of 56 withoxalyl chloride and then ammonia gives 57 which are hydrolyzed toproduce 58. Compound 58b is converted to its sodium salt 59a whichyields 59b-k on reaction with the appropriate alkyl halide.

Compound 36b is O-alkylated to give 59l-p.

Pyridine 60 is N-alkylated by 2-haloketones to produce intermediatepyridinium compounds which are cyclized by base to give 61. Reaction of61 with acyl chlorides produces 62 which are reduced to 63 by tertbutylamine-borane and aluminum chloride. Sequential treatment of 63 withoxalyl chloride and then ammonia yields 64 which are O-demethylated byBBr₃ to give 65. The sodium salt of 65 is reacted with ethyl4-bromobutyrate to give 66 which is hydrolyzed to the acid 67.

Compounds 36d and 65c are O-alkylated by omega-bromocarboxylic esters togive 68 which are hydrolyzed to the acids 69. Compounds 36d and 65cproduce 70 on treatment with propiolactone and base.

Compounds 66 are reduced to 71 by tert-butylamine-borane and aluminumchloride.

Pyridine 44b reacts with ethyl bromoacetate to produce 72 which istreated with CS₂ and base and then with ethyl acrylate to form 73.Reaction of 73 with base and ethyl bromoacetate yields a mixture ofregioisomers 74a+b, 6- and 8-benzyloxy compounds. Base treatment of74a+b eliminates ethyl acrylate to form 75 which is separated from theisomer of 6-benzyloxy derivative and S-alkylated to give 76. Hydrolysisof 76 forms 77 which is thermally decarboxylated to yield 78. Compound78 is C-alkylated to form 79 which on sequential treatment with oxalylchloride and then ammonia forms 80. Ether cleavage of 80 gives 81 whosesodium salt is alkylated by methyl bromoacetate to form 82 which arehydrolyzed to acids 83.

Aminopicoline 84 is converted to its N-CBZ derivative 85 whose anion isalkylated by-methyl bromoacetate to produce 86. Reaction of 86 withmethyl alpha-bromoalkyl ketones in the presence of base yields 87.Sequential treatment of 87 with oxalyl chloride and then ammonia gives88 which is converted to 89 by hydrogenolysis of the N-CBZ function.Hydrolysis of 89 yields acids 90.

Compounds 88 are reduced by tert-butylamine-borane and aluminum chlorideto 91 which are hydrolyzed to acids 92.

Pyridine 24 is N-alkylated by methyl bromoacetate, cyclized with base,and o-methylated using dimethysulfate to give 94. Hydrolysis of theester function of 94 followed by thermal decarboxylation yields2-methoxy-8-benzyloxyindolizine which is C-alkylated at position 3 andthen reacted sequentially with oxalyl chloride and ammonia to produce95. Hydrogenolysis of the 8-benzyloxy group followed by O-alkylationgives 96 which is hydrolyzed to 97.

f) Indene sPLA₂ inhibitors as described in U.S. patent application Ser.No. 08/776618 filed Jul. 20, 1995, (titled, Synovial Phospholipase A2Inhibitor Compounds having an Indene Type Nucleus, PaarmaceuticalFormulations Containing said Compounds, and Therapeutic Methods of UsingSaid Compounds”), the entire disclosure of which is incorporated hereinby reference, are useful in practicing the method of the invention.

The method of the invention is for treatment of a mammal, including ahuman, afflicted with a non-rheumatoid arthritis, said method comprisingadministering to said human a therapeutically effective amount of anindene-1-acetamide compound or a pharmaceutically acceptable salt,solvate or prodrug derivative thereof; wherein said compound isrepresented by the formula (If);

wherein;

X is oxygen or sulfur;

each R₁ is independently hydrogen, C₁-C₃ alkyl, or halo;

R₃ is selected from groups (a), (b) and (c) where;

(a) is C₇C₂₀ alkyl, C₇-C₂₀ alkenyl, C₇-C₂₀ alkynyl, carbocyclic radical,or heterocyclic radical, or

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents; or

(c) is the group —(L)—R₈₀; where, —(L)— is a divalent linking group of 1to 12 atoms and where R₈₀ is a group selected from (a) or (b);

R₂ is hydrogen, halo, C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl,—O—(C₁-C₂ alkyl), —S—(C₁-C₂ alkyl), or a non-interfering substituenthaving a total of 1 to 3 atoms other than hydrogen;

R₆ and R₇ are independently selected from hydrogen, a non-interferingsubstituent, or the group, —(L_(a))-(acidic group); wherein —(L_(a))—,is an acid linker having an acid linker length of 1 to 10; provided,that at least one of R₆ and R₇ must be the group, —(L_(a))-(acidicgroup); and

R₄ and R₅ are each independently selected from hydrogen, non-interferingsubstituent, carbocyclic radical, carbocyclic radical substituted withnon-interfering substituents, heterocyclic radical, and heterocyclicradical substituted with non-interfering substituents.

Suitable indene compounds also include the following:

An indene-1-acetic acid hydrazide compound or a pharmaceuticallyacceptable salt, solvate or prodrug derivative thereof; wherein saidcompound is represented by the formula (IIf);

 wherein:

X is oxygen or sulfur;

each R₁ is independently hydrogen, C₁-C₃ alkyl, or halo;

R₃ is selected from groups (a), (b) and (c) where;

(a) is C₇-C₂₀ alkyl, C₇-C₂₀ alkenyl, C₇-C₂₀ alkynyl, carbocyclicradical, or heterocyclic radical, or

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents; or

(c) is the group —(L)—R₈₀; where, —(L)— is a divalent linking group of 1to 12 atoms and where R₈₀ is a group selected from (a) or (b);

R₂ is hydrogen, halo, C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl,—O—(C₁-C₂ alkyl), —S—(C₁-C₂ alkyl), or a non-interfering substituenthaving a total of 1 to 3 atoms other than hydrogen;

R₆ and R₇ are independently selected from hydrogen, a non-interferingsubstituent, or the group, —(L_(a))-(acidic group); wherein —(L_(a))—,is an acid linker having an acid linker length of 1 to 10; provided,that at least one of R₆ and R₇ must be the group, —(L_(a))-(acidicgroup); and

R₄ and R₅ are each independently selected from hydrogen, non-interferingsubstituent, carbocyclic radical, carbocyclic radical substituted withnon-interfering substituents, heterocyclic radical, and heterocyclicradical substituted with non-interfering substituents.

Suitable indene compounds for use in the method of the invention alsoinclude the following:

An indene-1-glyoxylamide compound or a pharmaceutically acceptable salt,solvate or prodrug derivative thereof; wherein said compound isrepresented by the formula (IIIf);

X is oxygen or sulfur;

R₃ is selected from groups (a), (b) and (c) where;

(a) is C₇-C₂₀ alkyl, C₇-C₂₀ alkenyl, C₇-C₂₀ alkynyl, carbocyclicradical, or heterocyclic radical, or

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents; or

(c) is the group —(L)—R₈₀; where, —(L)— is a divalent linking group of 1to 12 atoms and where R₈₀ is a group selected from (a) or (b);

R₂ is hydrogen, halo, C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl,—O—(C₁-C₂ alkyl), —S—(C₁-C₂ alkyl), or a non-interfering substituenthaving a total of 1 to 3 atoms other than hydrogen;

R₆ and R₇ are independently selected from hydrogen, a non-interferingsubstituent, or the group, —(L_(a))-(acidic group); wherein —(L_(a))—,is an acid linker having an acid linker length of 1 to 10; provided,that at least one of R₆ and R₇ must be the group, —(L_(a))-(acidicgroup);

R₄ and R₅ are each independently selected from hydrogen, non-interferingsubstituent, carbocyclic radical, carbocyclic radical substituted withnon-interfering substituents, heterocyclic radical, and heterocyclicradical substituted with non-interfering substituents.

The method of making the indene compounds is as follows:

A mixture of an anisaldehyde 1, propionic anhydride, and sodiumpropionate is heated to produce 2 which is reduced by hydrogen in thepresence of Pd/c to give 3. Acid cyclization of 3 yields 6.Alternatively, the aromatic position para to the methoxy group of 3 isblocked by bromination to give 4 which is cyclized to 5 by acid and thendebrominated using hydrogen and Pd/C to give 6. Reaction of 6 with theanion of triethyl phosphonoacetate produces 7 and/or 8. Radicalbromination of 8 gives 9, which on reduction with hydrogen in thepresence of PtO₂ yields 7. Alternatively, treatment of 8 with acid gives7.

Scheme-2

a: R = Ph R^(a) = Me 6-R^(b)O n = 3 b: R = Ph R^(a) = Me 7-R^(b)O n = 1c: R = Ph R^(a) = Et 7-R^(b)O n = 1 d: R = o-Ph—Ph R^(a) = Et 7-R^(b)O n= 1 e: R = o-Bn—Ph R^(a) = Et 7-R^(b)O n = 1 f: R = m-Cl—Ph R^(a) = Et7-R^(b)O n = 1 g: R = o,m-di-Cl—Ph R^(a) = Et 7-R^(b)O n = 1 h: R =m-CF₃—Ph R^(a) = Et 7-R^(b)O n = 1 i: R = 1-Naphthyl R^(a) = Et 7-R^(b)On = 1 j: R = 2-Naphthyl R^(a) = Et 7-R^(b)O n = 1 where R^(b) is—(CH₂)_(n)COOH

Compound 7 is condensed with benzaldehyde and its derivatives in thepresence of base to give 10. Indenes 10 are converted to an active esterusing benzotriazo-1-yloxytris(dimethylamino) hexafluorophosphonate andthen reacted with ammonium hydroxide to form 11. Demethylation of 11with BBr₃ forms 12 which is O-alkylated using sodium hydride and anomega-bromoalkanoic acid ester to produce 13. Aqueous base hydrolysis of13 yields 14.

Compound 12c is O-alkylated using sodium hydride and methylbromoacetateto product 15 which is reduced by hydrogen in the presence of Pd/C togive a mixture of isomers 16a and 16b. Aqueous base hydrolysis of 16aand 16b gives 17a and 17b respectively.

Compound 10d is treated with lithium diisopropylamine, then air isbubbled into the solution to give 18. The indene 18 is converted to anactive ester usingbenzotriazo-1-yloxytris(dimethylamino)hexafluorophosphonate and thenreacted with ammonium hydroxide.to form the hydroxy acetamide 19.Compound 19 is oxidized to 20 using N-methylmorpholine N-oxide in thepresence of tetrapropylammonium perruthenate.

g) Carbazole and tetrahydrocarbazole sPLA₂ inhibitors and methods ofmaking these compounds are set out in U.S. patent application Ser. No.09/063066 filed Apr. 21, 1998 (titled, “Substituted Carbazoles and1,2,3,4-Tetrahydrocarbazoles”), the entire disclosure of which isincorporated herein by reference. The method of the invention includestreatment of a mammal with these compounds.

The method of the invention is for treatment of a mammal, including ahuman, afflicted with a non-rheumatoid arthritis, said method comprisingadministering to said human a therapeutically effective amount carbazoleor tetrahydrocarbazole represented by the following:

A compound of the formula (Ie)

wherein;

A is phenyl or pyridyl wherein the nitrogen is at the 5-, 6-, 7- or8-position;

one of B or D is nitrogen and the other is carbon;

Z is cyclohexenyl, phenyl, pyridyl, wherein the nitrogen is at the 1-,2-, or 3-position, or a 6-membered heterocyclic ring having oneheteroatom selected from the group consisting of sulfur or oxygen at the1-, 2- or 3-position, and nitrogen at the 1-, 2-, 3- or 4-position;

---- is a double or single bond;

R²⁰ is selected from groups (a), (b) and (c) where;

(a) is —(C₅-C₂₀)alkyl, —(C₅-C₂₀)alkenyl, (C₅-C₂₀)alkynyl, carbocyclicradicals, or heterocyclic radicals, or

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents; or

(c) is the group —(L)—R⁸⁰; where, —(L)— is a divalent linking group of 1to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, andsulfur; wherein the combination of atoms in —(L)— are selected from thegroup consisting of (i) carbon and hydrogen only, (ii) one sulfur only,(iii) one oxygen only, (iv) one or two nitrogen and hydrogen only, (v)carbon, hydrogen, and one sulfur only, and (vi) and carbon, hydrogen,and oxygen only; and where R⁸⁰ is a group selected from (a) or (b);

R²¹ is a non-interfering substituent;

R1′ is —NHNH₂, —NH₂ or —CONH₂;

R^(2′) is selected from the group consisting of —OH, and—O(CH₂)_(t)R^(5′) where

R^(5′) is H, —CN, —NH₂, —CONH₂, —CONR⁹R¹⁰—NHSO₂R¹⁵; —CONHSO₂R¹⁵, whereR¹⁵ is —(C₁-C₆)alkyl or —CF₃; phenyl or phenyl substituted with —CO₂H or—CO₂(C₁-C₄)alkyl; and —(L_(a))-(acidic group), wherein —(L_(a))— is anacid linker having an acid linker length of 1 to 7 and t is 1-5;

R³′ is selected from non-interfering substituent, carbocyclic radicals,carbocyclic radicals substituted with non-interfering substituents,heterocyclic radicals, and heterocyclic radicals substituted withnon-interfering substituents; or a pharmaceutically acceptable racemate,solvate, tautomer, optical isomer, prodrug derivative or salt thereof;

provided that; when R^(3′) is H, R²⁰ is benzyl and m is 1 or 2; R^(2′)cannot be —O(CH₂)_(m)H; and

provided that when D is nitrogen, the heteroatom of Z is selected fromthe group consisting of sulfur or oxygen at the 1-, 2- or 3-position andnitrogen at the 1-, 2-, 3- or 4-position.

Preferred in the practice of the method of the invention are compoundsrepresented by the formula (IIe):

wherein;

Z is cyclohexenyl, or phenyl;

R²¹ is a non-interfering substituent;

R¹ is —NHNH₂ or —NH₂;

R² selected from the group consisting of —OH and —O(CH₂)_(m)R⁵ where

R⁵ is H, —CO₂H, —CONH₂, —CO₂(C₁-C₄ alkyl);

 where R⁶ and R⁷ are each independently —OH or —O(C₁-C₄)alkyl; —SO₃H,—SO₃(C1-C4 alkyl), tetrazolyl, —CN, —NH₂, —NHSO₂R¹⁵; —CONHSO₂R¹⁵, whereR¹⁵ is —(C₁-C₆)alkyl or —CF₃, phenyl or phenyl substituted with —CO₂H or—CO₂(C₁-C₄)alkyl where m is 1-3;

R³ is H, —O(C₁-C₄)alkyl, halo, —(C₁-C₆)alkyl, phenyl,—(C₁-C₄)alkylphenyl; phenyl substituted with —(C₁-C₆)alkyl, halo, or—CF₃; —CH₂OSi(C₁-C₆)alkyl, furyl, thiophenyl, —(C₁-C₆)hydroxyalkyl; or—(CH₂)_(n)R⁸ where R⁸ is H, —CONH₂, —NR⁹R¹⁰, —CN or phenyl where R⁹ andR¹⁰ are independently —(C₁-C₄)alkyl or -phenyl(C₁-C₄)alkyl and n is 1 to8;

R⁴ is H, —(C₅-C₁₄)alkyl, —(C₃-C₁₄)cycloalkyl, pyridyl, phenyl or phenylsubstituted with —(C₁-C₆)alkyl, halo, —CF₃, —OCF₃, —(C₁-C₄)alkoxy, —CN,—(C₁-C₄)alkylthio, phenyl(C₁-C₄)alkyl, —(C₁-C₄)alkylphenyl, phenyl,phenoxy or naphthyl;

or a pharmaceutically acceptable racemate, solvate, tautomer, opticalisomer, prodrug derivative or salt, thereof.

Preferred specific compounds including all salts and prodrug derivativesthereof, for practicing the method of the invention are as follows:

9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-carboxylic acidhydrazide;

9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide;

[9-benzyl-4-carbamoyl-7-methoxy-1,2,3,4-tetrahydrocarbazol-5-yl]oxyaceticacid sodium salt;

[9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl]oxyacetic acid;

methyl [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl]oxyacetic acid;

9-benzyl-7-methoxy-5-cyanomethyloxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide;

9-benzyl-7-methoxy-5-(1H-tetrazol-5-yl-methyl)oxy)-1,2,3,4-tetrahydrocarbazole-4-carboxamide;

{9-[(phenyl)methyl]-5-carbamoyl-2-methyl-carbazol-4-yl}oxyacetic acid;

{9-[(3-fluorophenyl)methyl]-5-carbamoyl-2-methyl-carbazol-4-yl}oxyaceticacid;

{9-[(3-methylphenyl)methyl]-5-carbamoyl-2-methyl-carbazol-4-yl}oxyaceticacid;

{9-[(phenyl)methyl]-5-carbamoyl-2-(4-trifluoromethylphenyl)carbazol-4-yl}oxyaceticacid;

9-benzyl-5-(2-methanesulfonamido)ethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide;

9-benzyl-4-(2-methanesulfonamido)ethyloxy-2-methoxycarbazole-5-carboxamide;

9-benzyl-4-(2-trifluoromethanesulfonamido)ethyloxy-2-methoxycarbazole-5-carboxamide;

9-benzyl-5-methanesulfonamidoylmethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide;

9-benzyl-4-methanesulfonamidoylmethyloxy-carbazole-5-carboxamide;

[5-carbamoyl-2-pentyl-9-(phenylmethyl)carbazol-4-yl]oxyacetic acid;

[5-carbamoyl-2-(1-methylethyl)-9-(phenylmethyl)carbazol-4-yl]oxyaceticacid;

[5-carbamoyl-9-(phenylmethyl)-2-[(tri(-1-methylethyl)silyl)oxymethyl]carbazol-4-yl]oxyaceticacid;

[5-carbamoyl-2-phenyl-9-(phenylmethyl)carbazol-4-yl]oxyaceticacid[5-carbamoyl-2-(4-chlorophenyl)-9-(phenylmethyl)carbazol-4-yl]oxyaceticacid;

[5-carbamoyl-2-(2-furyl)-9-(phenylmethyl)carbazol-4-yl]oxyacetic acid;

[5-carbamoyl-9-(phenylmethyl)-2-[(tri(-1-methylethyl)silyl)oxymethyl]carbazol-4-yl]oxyaceticacid, lithium salt;

{9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(3-phenoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(2-Fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyaceticacid;

{9-[(2-benzylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(3-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyaceticacid;

{9-[(1-naphthyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(2-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(3,5-dimethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(3-iodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(2-Chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(2,3-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(2,6-dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(3-trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyaceticacid;

{9-[(2-biphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(2-Biphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

the {9-[(2-Biphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

[9-Benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbaole-5-yl]oxyacetic acid;

{9-[(2-Pyridyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

{9-[(3-Pyridyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;

[9-benzyl-4-carbamoyl-8-methyl-1,2,3,4-tetrahydrocarbazol-5-yl]oxyaceticacid;

[9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl]oxyacetic acid;

[9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-5-yl]oxyaceticacid;

[9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl]oxyacetic acid;

[9-benzyl-4-carbamoyl-8-chloro-1,2,3,4-tetrahydrocarbazol-5-yl]oxyaceticacid;

[9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl]oxyacetic acid;

[9-[(Cyclohexyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic acid;

[9-[(Cyclopentyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic acid;

5-carbamoyl-9-(phenylmethyl)-2-[[(propen-3-yl)oxy]methyl]carbazol-4-yl]oxyaceticacid;

[5-carbamoyl-9-(phenylmethyl)-2-[(propyloxy)methyl]carbazol-4-yl]oxyaceticacid;

9-benzyl-7-methoxy-5-((carboxamidomethyl)oxy)-1,2,3,4-tetrahydrocarbazole-4-carboxamide;

9-benzyl-7-methoxy-5-cyanomethyloxy-carbazole-4-carboxamide;

9-benzyl-7-methoxy-5-((1H-tetrazol-5-yl-methyl)oxy)carbazole-4-carboxamide;

9-benzyl-7-methoxy-5-((carboxamidomethyl)oxy)-carbazole-4-carboxamide;and

[9-Benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbaole-5-yl]oxyacetic acid

or a pharmaceutically acceptable racemate, solvate, tautomer, opticalisomer, prodrug derivative or salt, thereof.

Other desireable carbazole compounds suitable for practicing the methodof thein invention are selected from those represented by the formula(XXX):

wherein:

R¹ is —NHNH₂, or —NH₂;

R² is selected from the group consisting of —OH and —O(CH₂)_(m)R⁵ where

R⁵ is H, —CO₂H, —CO₂(C1-C4 alkyl);

 where R⁶ and R⁷ are each independently —OH or —O(C₁-C₄)alkyl; —SO₃H,—SO₃(C₁-C₄ alkyl), tetrazolyl, —CN, —NH₂, —NHSO₂R¹⁵; —CONHSO₂R¹⁵, whereR¹⁵ is —(C₁-C₆)alkyl or —CF₃, phenyl or phenyl substituted with —CO2H or—CO₂(C₁-C₄)alkyl where m is 1-3;

R³ is H, —O(C₁-C₄)alkyl, halo, —(C₁-C₆)alkyl, phenyl,—(C₁-C₄)alkylphenyl; phenyl substituted with —(C₁-C₆)alkyl, halo, or—CF₃; —CH₂OSi(C₁-C₆)alkyl, furyl, thiophenyl, —(C₁-C₆)hydroxyalkyl; or—(CH₂)_(n)R⁸ where R⁸ is H, —CONH₂, —NR⁹R¹⁰, —CN or phenyl where R⁹ andR¹⁰ are independently —(C₁-C₄)alkyl or -phenyl(C₁-C₄)alkyl and n is 1 to8;

R⁴ is H, —(C₅-C₁₄)alkyl, —(C₃-C₁₄)cycloalkyl, pyridyl, phenyl or phenylsubstituted with —(C₁-C₆)alkyl, halo, —CF₃, —OCF₃, —(C₁-C₄)alkoxy, —CN,—(C₁-C₄)alkylthio, phenyl(C1-C₄)alkyl, —(C₁-C₄)alkylphenyl, phenyl,phenoxy or naphthyl;

A is phenyl or pyridyl wherein the nitrogen is at the 5-, 6-, 7- or8-position;

Z is cyclohexenyl, phenyl, pyridyl wherein the nitrogen is at the 1-, 2-or 3-position or a 6-membered heterocyclic ring having one heteroatomselected from the group consisting of sulfur or oxygen at the 1-, 2- or3-position and nitrogen at the 1-, 2-, 3- or 4-position, or

wherein one carbon on the heterocyclic ring is optionally substitutedwith ═O;

or a pharmaceutically acceptable racemate, solvate, tautomer, opticalisomer, prodrug derivative or salt thereof;

provided that one of A or Z is a heterocyclic ring.

Further desirable specific compounds suitable for the method of theinvention are selected from the following:

(R,S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl)oxyaceticacid;(R,S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl)oxyaceticacid;[N-benzyl-1-carbamoyl-1-aza-1,2,3,4-tetrahydrocarbazol-8-yl]oxyaceticacid;4-methoxy-6-methoxycarbonyl-10-phenylmethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole;(4-carboxamido-9-phenylmethyl-4,5-dihydrothiopyrano[3,4-b]indol-5-yl)oxyaceticacid;3,4-dihydro-4-carboxamidol-5-methoxy-9-phenylmethylpyrano[3,4-b]indole;2-[(2,9bis-benzyl-4-carbamoyl-1,2,3,4-tetrahydro-beta-carbolin-5-yl)oxy]aceticacid or a pharmaceutically acceptable racemate, solvate, tautomer,optical isomer, prodrug derivative or salt thereof.

Particularly preferred compounds for the treatment of non-rheumatoidarthritis are represented by the formulae (Xe) and (XIe) below:

For all of the above compounds of the carbazole or tetrahydrocarbazoletype it is advantageous to use them in their (i)acid form, or (ii)pharmaceutically acceptable (e.g., Na, K) form, or (iii) and prodrugsderivatives (e.g., methyl ester, ethyl ester, n-butyl ester, morpholinoethyl ester).

Prodrugs are derivatives of sPLA2 inhibitors used in the method of theinvention which have chemically or metabolically cleavable groups andbecome by solvolysis or under physiological conditions the compounds ofthe invention which are pharmaceutically active in vivo. Derivatives ofthe compounds of this invention have activity in both their acid andbase derivative forms, but the acid derivative form often offersadvantages of solubility, tissue compatibility, or delayed release in amammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9,2-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives wellknown to practitioners of the art, such as, for example, esters preparedby reaction of the parent acidic compound with a suitable alcohol, oramides prepared by reaction of the parent acid compound with a suitableamine. Simple aliphatic or aromatic esters derived from acidic groupspendent on the compounds of this invention are preferred prodrugs. Insome cases it is desirable to prepare double ester type prodrugs such as(acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Specificpreferred prodrugs are ester prodrugs inclusive of methyl ester, ethylester, n-propyl ester, isopropyl ester, n-butyl ester, sec-butyl,tert-butyl ester, N,N-diethylglycolamido ester, and morpholino-N-ethylester. Methods of making ester prodrugs are disclosed in U.S. Pat. No.5,654,326. Additional methods of prodrug synthesis are disclosed in U.S.Provisional Patent Application Serial No. 60/063280 filed Oct. 27, 1997(titled, N,N-diethylglycolamido ester Prodrugs of Indole sPLA2Inhibitors), the entire disclosure of which is incorporated herein byreference; U.S. Provisional Patent Application Serial No. 60/063646filed Oct. 27, 1997 (titled, Morpholino-N-ethyl Ester Prodrugs of IndolesPLA2 Inhibitors), the entire disclosure of which is incorporated hereinby reference; and U.S. Provisional Patent Application Serial No.60/063284 filed Oct. 27, 1997 (titled, Isopropyl Ester Prodrugs ofIndole sPLA2 Inhibitors), the entire disclosure of which is incorporatedherein by reference.

Carbazole and tetrahydrocarbazole sPLA₂ inhibitor compounds useful forpracticing the method of the invention may be made by the followinggeneral methods:

The compounds of formula Ie where Z is cyclohexene are preparedaccording to the following reaction Schemes I(a) and (c).

Wherein;

R¹ is —NH₂, R³(a) is H, —O(C₁-C₄)alkyl, halo, —(C₁-C₆)alkyl, phenyl,—(C₁-C₄)alkylphenyl; phenyl substituted with —(C₁-C₆)alkyl, halo, or—CF₃; —CH₂OSi(C₁-C₆)alkyl, furyl, thiophenyl, —(C₁-C₆)hydroxyalkyl,—(C₁-C₆)alkoxy(C₁-C₆)alkyl, —(C₁-C₆)alkoxy(C₁-C₆)alkenyl; or—(CH₂)_(n)R⁸ where R⁸ is H, —CONH₂, —NR⁹R¹⁰, —CN or phenyl where R⁹ andR¹⁰ are independently hydrogen, —CF₃, phenyl, —(C₁-C₄)alkyl,—(C₁-C₄)alkylphenyl or —phenyl(C₁-C₄)alkyl and n is 1 to 8;

when R¹ is —NHNH₂, R³(a) is H, —O(C₁-C₄)alkyl, halo, —(C₁-C₆)alkyl,phenyl, —(C₁-C₄)alkylphenyl; phenyl substituted with —(C₁-C₆)alkyl, haloor —CF₃; —CH₂OSi(C₁-C₆)alkyl, furyl, thiophenyl, —(C₁-C₆)hydroxyalkyl,—(C₁-C₆)alkoxy(C₁-C₆)alkyl, —(C₁-C₆)alkoxy(C₁-C₆)alkenyl; or—(CH₂)_(n)R⁸ where R⁸ is H, —NR⁹R¹⁰, —CN or phenyl where R⁹ and R¹⁰ areindependently hydrogen, —CF₃, phenyl, —(C₁-C₄)alkyl, —(C₁-C₄)alkylphenylor -phenyl(C₁-C₄)alkyl and n is 1 to 8;

R^(2(a)) is —OCH₃ or —OH.

An appropriately substituted nitrobenzene (1) can be reduced to theaniline (2) by treatment with a reducing agent, such as hydrogen in thepresence of Pd/C, preferably at room temperature.

Compound (2) is N-alkylated at temperatures of from about 0 to 20° C.using an alkylating agent such as an appropriately substituted aldehydeand sodium cyanoborohydride to form (3). Alternately, an appropriatelysubstituted benzyl halide may be used for the first alkylation step. Theresulting intermediate is further N-alkylated by treatment with2-carbethoxy-6-bromocyclohexanone, preferably at temperatures of about80° C. to yield (4) or by treatment with potassium hexamethyldisilazideand the bromoketoester.

The product (4) is cyclized to the tetrahydrocarbazole (5) by refluxingwith ZnCl₂ in benzene for from about 1 to 2 days, preferably at 80° C.(Ref 1). Compound (5) is converted to the hydrazide (6) by treatmentwith hydrazine at temperatures of about 100° C., or to the amide (7) byreacting with methylchloroaluminum amide in benzene. (Ref 2)Alternatively, (7) may be produced by treatment of (6) with Raney nickelactive catalyst.

It will be readily appreciated that when R^(3(a)) is:

conversion to the amide will also be achieved in this procedure.

Compounds (6) and (7) may be dealkylated, preferably at 0° C. to roomtemperature, with a dealkylating agent, such as boron tribromide orsodium thioethoxide, to give compound (7) where R^(2(a)) is —OH, whichmay then be further converted to compound (9), by realkylating with abase, such as sodium hydride, and an alkylating agent, such asBr(CH₂)_(m)R⁵, where R⁵ is the carboxylate or phosphonic diester ornitrile as defined above. Conversion of R² to the carboxylic acid may beaccomplished by treatment with an aqueous base. When R² is nitrile,conversion to the tetrazole may be achieved by reacting with tri-butyltin azide or conversion to the carboxamide may be achieved by reactingwith basic hydrogen peroxide. When R² is the phosphonic diester,conversion to the acid may be achieved by reacting with a dealkylatingagent such as trimethylsilyl bromide. The monoester may be accomplishedby reacting the diester with an aqueous base.

When R² and R³ are both methoxy, selective demethylation can be achievedby treating with sodium ethanethiolate in dimethylformamide at 100° C.

Ref 1 Julia, M.; Lenzi, J. Preparation d'acidestetrahydro-1,2,3,4-carbazole-1 ou -4. Bull.Soc.Chim.France, 1962,226-2263.

Ref 2 Levin, J. I.; Turos, E.; Weinreb, S. M. An alternative procedurefor the aluminum-mediated conversion of esters to amides. Syn.Comm.,1982, 12, 989-993.

An alternative synthesis of intermediate (5) is shown in Scheme I(b), asfollows.

where

PG is a protecting group;

R^(3a) is as defined in Scheme 1, above.

The aniline (2) is N-alkylated with 2-carbethoxy-6-bromocyclohexanone indimethyl formamide in the presence of sodium bicarbonate for 8-24 hoursat 50° C. Preferred protecting groups include methyl, carbonate, andsilyl groups, such as t-butyldimethylsilyl. The reaction product (4′) iscyclized to (5′) using the ZnCl₂ in benzene conditions described inScheme I(a), above. N-alkylation of (5′) to yield (5) is accomplished bytreatment with sodium hydride and the appropriate alkyl halide indimethylformamide at room temperature for 4-8 hours.

R^(3(a)) is as defined in Scheme I.

As discussed in Scheme I above, carbazole (5) is hydrolyzed to thecarboxylic acid (10) by treatment with an aqueous base, preferably atroom temperature to about 100° C. The intermediate is then converted toan acid chloride utilizing, for example, oxalyl chloride anddimethylformamide, and then further reacted with a lithium salt of (S)or (R)-4-alkyl-2-oxazolidine at a temperature of about −75° C., to give(11a) and (11b), which are separable by chromatography.

The diastereomers are converted to the corresponding enantiomeric benzylesters (12) by brief treatment at temperatures of about 0° C. to roomtemperature with lithium benzyl oxide. (Ref 3) The esters (12) are thenconverted to (7) preferably by treatment with methylchloroaluminum amide(Ref 2, above) or, alternately, by hydrogenation using, for example,hydrogen and palladium on carbon, as described above, to make the acidand then reacting with an acyl azide, such as diphenylphosphoryl azidefollowed by treatment with ammonia. Using the procedure described abovein Scheme I, compound (9a) or (9b) may be accomplished.

Ref 3 Evans, D. A.; Ennis, M. D.; Mathre, D. J. Asymmetric alkylationreactions of chiral imide enolates. A practical approach to theenantioselective synthesis of alpha-substituted carboxylic acidderivatives. J.Am.Chem.Soc., 1982, 104, 1737-1738.

Compounds of formula Ie where Z is phenyl can be prepared as follows inSchemes III(a)-(f), below.

A 1,2,3,4-tetrahydrocarbazole-4-carboxamide or 4-carboxhydrazide (13) isdehydrogenated by refluxing in a solvent such as carbitol in thepresence of Pd/C to produce the carbazole-4-carboxamide. Alternately,treatment of (13) with DDQ in an appropriate solvent such as dioxaneyields carbozole (14).

Depending on the substituent pattern oxidation as described above mayresult in de-alkylation of the nitrogen. For example when R³ issubstituted at the 8-position with methyl, oxidation results indealkylation of the nitrogen which may be realkylated by treatment withsodium hydride and the appropriate alkyl halide as described in SchemeI(a) above to prepare the deired product (14).

Benzoic acid derivative(16) where X is preferably chlorine, bromine oriodine and the protecting group is preferably —CH₃, are reduced to thecorresponding aniline (25) with a reducing agent, such as stannouschloride in the presence of acid under the general conditions ofSakamoto et al, Chem Pharm. Bull. 35 (5), 1823-1828 (1987).

Alternatively, reduction with sodium dithionite in the presence of abase, such as sodium carbonate in a noninterferring solvent, such aswater, ethanol, and/or tetrahydrofuran affords starting material (16).

Alternatively, reduction by hydrogenation over a sulfided platinumcatalyst supported on carbon with hydrogen at 1 to 60 atmospheres in anoninterfering solvent, preferably ethyl acetate, to form a startingmaterial (16).

The reactions are conducted at temperatures from about 0 to 100° C.preferably at ambient temperature, and are substantially complete inabout 1 to 48 hours depending on conditions.

The aniline (25) and dione (15) are condensed under dehydratingconditions, for example, using the general procedure of Iida, et al.,(Ref 5), with or without a noninterfering solvent, such as toluene,benzene, or methylene chloride, under dehydrating conditions at atemperature about 10 to 150° C. The water formed in the process can beremoved by distillation, azetropic removal via a Dean-Stark apparatus,or the addition of a drying agent, such as molecular sieves, magnesiumsulfate, calcium carbonate, sodium sulfate, and the like.

The process can be performed with or without a catalytic amount of anacid, such a p-toluenesulfonic acid or methanesulfonic acid. Otherexamples of suitable catalysts include hydrochloric acid, phenylsulfonicacid, calcium chloride, and acetic acid.

Examples of other suitable solvents include tetrahydrofuran, ethylacetate, methanol, ethanol, 1,1,2,2-tetrachloroethane, chlorobenzene,bromobenzene, xylenes, and carbotetrachloride.

The condensation of the instant process is preferably carried out neat,at a temperature about 100 to 150° C. with the resultant water removedby distillation via a stream of inert gas, such as, nitrogen or argon.

The reaction is substantially complete in about 30 minutes to 24 hours.

Intermediate (26) may then be readily cyclized in the presence of apalladium catalyst, such as Pd(OAc)₂ or Pd(PPh₃)₄ and the like, aphosphine, preferably a trialkyl- or triarylphosphine, such astriphenylphosphine, tri-o-tolylphosphine or tricyclohexylphosphine, andthe like, a base, such as, sodium bicarbonate, triethylamine, ordiisopropylethylamine, in a noninterfering solvent, such as,acetonitrile, triethylamine, or toluene at a temperature about 25 to200° C. to form (19).

Examples of other suitable solvents include tetrahydrofuran, benzene,dimethylsulfoxide, or dimethylformamide.

Examples of other suitable palladium catalysts include Pd(PPh₃)Cl₂,Pd(OCOCF₃)₂, [(CH₃C₆H₄)₃P]₂PdCl₂, [(CH₃CH₂)₃P]₂PdCl₂, [(C₆H₁₁)₃P]₂PdCl₂,and [(C₆H₅)₃P]₂PdBr₂.

Examples of other suitable phosphines include triisopropylphosphine,triethylphosphine, tricyclopentylphosphine,1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, and1,4-bis(diphenylphosphino)butane.

Examples of other suitable bases include tripropyl amine,2,2,6,6-tetramethylpiperidine, 1,5-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene, (DBN) sodium carbonate, potassiumcarbonate, and potassium bicarbonate.

The cyclization of the instant process is preferably carried out withpalladium(II)acetate as catalyst in the presence of eithertriphenylphosphine, tri-o-tolylphosphine,1,3-bis(diphenylphosphino)propane, or tricyclohexylphosphine inacetonitrile as solvent and triethylamine as base at a temperature about50 to 150° C. The reaction is substantially complete in about 1 hour to14 days.

Alternatively, a preferred process for cyclization consists of thereaction of intermediate (26) with a palladacycle catalyst such astrans-di(μ-acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II)in a solvent such as dimethylacetamide (DMAC) at 120-140° C. in thepresence of a base such as sodium acetate.

Intermediate (19) may be alkylated with an alkylating agent XCH₂R₄,where X is halo in the presence of a base to form (20). Suitable basesinclude potassium carbonate, sodium carbonate, lithium carbonate, cesiumcarbonate, sodium bicarbonate, potassium bicarbonate, potassiumhydroxide, sodium hydroxide, sodium hydride, potassium hydride, lithiumhydride, and Triton B (N-benzyltrimethylammonium hydroxide).

The reaction may or may not be carried out in the presence of a crownether. Potassium carbonate and Triton B are preferred. The amount ofalkylating agent is not critical, however, the reaction is bestaccomplished using an excess of alkyl halide relative to the startingmaterial.

A catalytic amount of an iodide, such as sodium iodide or lithium iodidemay or may not be added to the reaction mixture. The reaction ispreferably carried out in an organic solvent, such as, acetone,dimethylformamide, dimethylsulfoxide, or acetonitrile. Other suitablesolvents include tetrahydrofuran, methyl ethyl ketone, and t-butylmethyl ether.

The reaction is conducted at temperatures from about −10 to 100° C.preferably at ambient temperature, and is substantially complete inabout 1 to 48 hours depending on conditions. Optionally, a phasetransfer reagent such as tetrabutylammonium bromide ortetrabutylammonium chloride may be employed.

Intermediate (20) May by dehydrogenated by oxidation with2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a noninterfering solvent toform (21).

Suitable solvents include methylene chloride, chloroform, carbontetrachloride, diethyl ether, methyl ethyl ketone, and t-butyl methylether. Toluene, benzene, dioxane, and tetrahydrofuran are preferredsolvents. The reaction is carried out at a temperature about 0 to 120°C. Temperatures from 50 to 120° C. are preferred. The reaction issubstantially complete in about 1 to 48 hours depending on conditions.

Intermediate (21) may be aminated with ammonia in the presence of anoninterfering solvent to form a (22). Ammonia may be in the form ofammonia gas or an ammonium salt, such as ammonium hydroxide, ammoniumacetate, ammonium trifluoroacetate, ammonium chloride, and the like.Suitable solvents include ethanol, methanol, propanol, butanol,tetrahydrofuran, dioxane, and water. A mixture of concentrated aqueousammonium hydroxide and tetrahydrofuran or methanol is preferred for theinstant process. The reaction is carried out at a temperature about 20to 100° C. Temperatures from 50 to 60° C. are preferred. The reaction issubstantially complete in about 1 to 48 hours depending on conditions.

Alkylation of (22) is achieved by treatment with an alkylating agent ofthe formula XCH₂R⁹ where X is halo and R⁷⁰ is —CO₂R⁷¹, —SO₃R⁷¹, —P(O)(OR⁷¹)₂, or —P(O) (OR⁷¹)H, where R⁷¹ is an acid protecting group or aprodrug function, in the presence of a base in a noninterfering solventto form (23). Methyl bromoacetate and t-butyl bromoacetate are thepreferred alkylating agents.

Suitable bases include potassium carbonate, sodium carbonate, lithiumcarbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate,potassium hydroxide, sodium hydroxide, sodium hydride, potassiumhydride, lithium hydride, and Triton B (N-benzyltrimethylammoniumhydroxide). The reaction may or may not be carried out in the presenceof a crown ether. Cesium carbonate and Triton B are preferred.

The amount of alkylating agent is not critical, however, the reaction isbest accomplished using an excess of alkyl halide relative to thestarting material. The reaction is preferably carried out in an organicsolvent, such as, acetone, dimethylformamide, dimethylsulfoxide, oracetonitrile. Other suitable solvents include tetrahydrofuran, methylethyl ketone, and t-butyl methyl ether.

The reaction is conducted at temperatures from about −10 to 100° C.preferably at ambient temperature, and is substantially complete inabout 1 to 48 hours depending on conditions. Optionally, a phasetransfer reagent such as tetrabutylammonium bromide ortetrabutylammonium chloride may be employed.

Intermediate (23) may be optionally hydrolyzed with a base or acid toform desired product (24) and optionally salified.

Hydrolysis of (23) is achieved using a base such as sodium hydroxide,potassium hydroxide, lithium hydroxide, aqueous potassium carbonate,aqueous sodium carbonate, aqueous lithium carbonate, aqueous potassiumbicarbonate, aqueous sodium bicarbonate, aqueous lithium bicarbonate,preferably sodium hydroxide and a lower alcohol solvent, such as,methanol, ethanol, isopropanol, and the like. Other suitable solventsinclude acetone, tetrahydrofuran, and dioxane.

Alternatively, the acid protecting group may be removed by organic andinorganic acids, such as trifluoroacetic acid and hydrochloric acid withor without a noninterferring solvent. Suitable solvents includemethylene chloride, tetrahydrofuran, dioxane, and acetone. The t-butylesters are preferably removed by neat trifluoroacetic acid.

The reaction is conducted at temperatures from about −10 to 100° C.preferably at ambient temperature, and is substantially complete inabout 1 to 48 hours depending on conditions.

The starting material (16) is prepared by esterifying compound (15) witha alkyl halide=XPG; where X is halo and PG is an acid protecting group,in the presence of a base, preferably potassium carbonate or sodiumcabonate, in a noninterferring solvent, preferably dimethylformamide ordimethylsulfoxide. The preferred alkyl halide is methyl iodide. Thereaction is conducted at temperatures from about 0 to 100° C. preferablyat ambient temperature, and is substantially complete in about 1 to 48hours depending on conditions.

Alternatively the starting material (16) may be prepared by condensationwith an alcohol HOPG, where PG is an acid protecting group, in thepresence of a dehydrating catalyst such as, dicyclohexylcarbodiimide(DCC) or carbonyl diimidazole.

In addition, U.S. Pat. No. 4,885,338 and Jpn. Kokai Tokkyo Koho05286912, November 1993 Hesei teach a method for preparing2-fluoro-5-methoxyaniline derivatives.

R is as defined in Scheme III(b),

R^(3(a)) is as defined in Scheme I(a), above; and

X is halo.

Benzoic acid derivatives (16) (X=Cl, Br, or I) and boronic acidderivative (27) (either commercially available or readily prepared byknown techniques from commercially available starting materials) arecondensed under the general procedure of Miyaura, et al., (Ref 8a) orTrecourt, et al., (Ref 8b) in the presence of a palladium catalyst, suchas Pd(Ph₃P)₄, a base, such as sodium bicarbonate, in an inert solvent,such as THF, toluene or ethanol, to afford compound (28).

Compound (28) is converted to the carbazole product (29) by treatmentwith a trialkyl or triaryl phosphite or phosphine, such as,triethylphosphite or triphenyl phosphine, according to the generalprocedure of Cadogan, et al. (Ref 6).

Compound (29) is N-alkylated with an appropriately substituted alkyl oraryl halide XCH₂R⁴ in the presence of a base, such as sodium hydride orpotassium carbonate, in a noninterfering solvent, such as toluene,dimethylformamide, or dimethylsulfoxide to afford carbazole (30).

Compound (30) is converted to the corresponding amide (22) by treatmentwith boron tribromide or sodium thioethoxide, followed by ammonia or anammonium salt, such as ammonium acetate, in an inert solvent, such aswater or alcohol, or with methylchloroaluminum amide in an inertsolvent, such as toluene, at a temperature between 0 to 110° C.

When R^(3(a)) is substituted at the 8-position with chloro,de-alkylation of (30) with boron tribromide results in de-benzylation ofthe nitrogen as described above. Alkylation may be readily accomplishedin a two step process. First, an O-alkylation by treatment with ahaloalkyl acetate such as methyl bromo acetate using sodium hydride intetrahydrofuran, followed by N-alkylation using for example a base suchas sodium hydride and an appropriately substituted alkyl or aryl halidein dimethoxy formamide. Compound (22) can be converted to productcarbazole product (24) as described previously in Scheme III(b) above.

Conversion to the desired prodrug may be accomplished by techniquesknown to the skilled artisan, such as for example, by treatment with aprimary or secondary halide to make an ester prodrug.

Alternatively, reduction of the nitro group of compound (28) with areducing agent, such as hydrogen in the presence of palladium on carbon,in a noninterfering solvent, such as ethanol, at 1 to 60 atmospheres, ata temperature of 0 to 60° C. affords the corresponding aniline (32).Compound (32) is converted to the carbazole (29) according to thegeneral procedure described by Trecourt, et al. (Ref 8b). The aniline istreated with sulfuric acid and sodium nitrite, followed by sodium azideto form an intermediate azide which is cyclized to carbazole (29) byheating in an inert sovent, such as toluene. Compound (29) is convertedto carbazole product (24) as described previously in Schemes III(b) andIII(c).

References

8)

a. N. Miyaura, et al., Synth. Commun. 11, 513 (1981)

b. F. Trecourt, et al., Tetrahedron, 51, 11743 6)

6) J. Cadogan et al., J. Chem. Soc., 4831 (1965)

In an aprotic solvent, preferably tetrahydrofuran, reduction of (40) isachieved using a reducing agent such as aluminum trihydride. Preferably,the reaction is conducted under inert atmosphere such as nitrogen, atroom temperature.

Sulfonylation may be achieved with an appropriate acylating agent in thepresence of an acid scavenger such as triethyl amine.

In a two-step, one-pot process, intermediate (50), prepared as describedin Scheme I(a) above, is first activated with an activating agent suchas carbonyl diimidazole. The reaction is preferably run in an aproticpolar or non-polar solvent such as tetrahydrofuran. Acylation with theactivated intermediate is accomplished by reacting with H₂NSOR¹⁵ in thepresence of a base, preferably diazabicycloundecene.

PG is an acid protecting group;

R²² is (C₁-C₆)alkoxy (C₁-C₆)alkyl is (C1-C₆)alkoxy (C₁-C₆)alkenyl

Starting material (20) is O-alkylated with an alkyl halide or alkenylhalide, using a base such as NaH, in an aprotic polar solvent preferablyanhydrous DMF, at ambient temperature under a nitrogen atmosphere. Theprocess of aromatization from a cyclohexenone functionality to a phenolfunctionality can be performed by treating the tetrahydrocabazoleintermediate (60) with a base such as NaH in the presence of methylbenzenesulfinate in an anhydrous solvent, such as 1,4-dioxane or DMF, toform the ketosulfoxide derivative. Upon heating at about 100° C. for 1-2hours, the ketosulfoxide derivative (60) is converted to the phenolderivative (61). Conversion of the ester (61) to the amide (62) can beachieved by treating a solution of (61) in an aprotic polar solvent suchas tetrahydrofuran with ammonia gas. Phenolic O-alkylation of (62) with,for example, methyl bromoacetate can be carried out in anhydrous DMF atambient temperature using Cs₂CO₃ or K₂CO₃ as a base to form (63).Desired product (64) can be derived from the basic hydrolysis of ester(63) using LiOH or NaOH as a base in an H₂O/CH₃OH/THF solution at 50° C.for 1-2 hours.

When R²² is —(C₁-C₆)alkoxy(C₁-C₆)alkenyl, hydrogenation of the doublebond can be performed by treating (63) in THF using PtO₂ as a catalysisunder a hydrogen atmosphere. Desired product can then be derived asdescribed above in Scheme III(g) from the basic hydrolysis of ester (63)using LIOH or NaOH as a base in an H₂O/CH₃OH/THF solution at 50° C. for1-2 hours.

Compounds of formula Ie where the A ring is phenyl and the heteroatom inZ is sulfur, oxygen or nitrogen can be prepared as described in SchemesIV(a)-(f), below.

PG is an acid protecting group.

X is halo.

R³(a) is H, —O(C₁-C₄)alkyl, halo, —(C₁-C₆)alkyl, phenyl,—(C₁-C₄)alkylphenyl; phenyl substituted with —(C₁-C₆)alkyl, halo or—CF³; —CH₂OSi(C₁-C₆)alkyl, furyl, thiophenyl, —(C₁-C₆)hydroxyalkyl; or—(CH₂)_(n)R⁸ where R⁸ is H, —NR⁹R¹⁰, —CN or phenyl where R⁹ and R¹⁰ areindependently —(C₁-C₄)alkyl or -phenyl(C₁-C₄)alkyl and n is 1 to 8;

An indole-3-acetic ester (101), Ref 10, is alkylated by treatment withalkalai metal amide and benzyloxymethyl chloride to give (102) which isconverted to the alcohol (103) by catalytic hydrogenation. The alcoholis alkylated to provide the formaldehyde acetal (104) which is cyclizedby Lewis acid to produce the pyrano[3,4-b]indole (105). The ester isconverted to the amide (106) by methylchloroaluminum amide, and then tothe phenol (107) with boron tribromide. The phenol is O-alkylated togive (108) which is hydrolyzed to the acid (109).

10) Dillard, R. et al., J, Med Chem. Vol 39, No. 26, 5119-5136.

PG is an acid protecting group

W is halo, alkyl or aryl sulfonyl

R³(a) is H, —O(C₁-C₄)alkyl, halo, —(C₁-C₆)alkyl, phenyl,—(C₁-C₄)alkylphenyl; phenyl substituted with —(C₁-C₆)alkyl, halo or—CF³; —CH₂OSi(C₁-C₆)alkyl, furyl, thiophenyl, —(C₁-C₆)hydroxyalkyl; or—(CH₂)_(n)R⁸ where R⁸ is H, —NR⁹R¹⁰, —CN or phenyl where R⁹ and R¹⁰ areindependently —(C₁-C₄)alkyl or -phenyl(C₁-C₄)alkyl and n is 1 to 8;

Reaction of this alcohol (103) with aldehyde and acid produces thepyranoindole (110).

Conversion of the hydroxyl function of (103) to a halide or sulfatefunctionality is achieved by treatment with triphenylphosphine and CH₃X(where X is a halogen) to make compounds of formula (111) where X is ahalide; or by treatment with triethylamine and methanesulfonyl chlorideto make the sulfonate. Displacement with the sodium salt of thiol aceticacid gives (114) which in turn is hydrolyzed by base to the thiol (115)which is reacted with an appropriately substituted aldehyde and acid toproduce the thiopyranoindoles (116).

Intermediate (111) may also be reacted with sodium azide to give theazido derivative (112) which is reduced by hydrogen catalytically togive the amine which is converted to the carboline (113) with aldehydeand acid.

Intermediates (113), (110) and (116) may be N-alkylated, using sodiumhydride and an appropriately substituted alkylhalide XCH₂R⁴.

4-Methoxyindole (117) is converted to the indole acetic acid derivative(118) by alkylation with an epoxy propionate. Treatment of (118) with abrominating reagent affords the mixture of bromo isomers (119) and (120)which give the Spiro compound (121) upon basic treatment. Heating (121)with benzyl bromide provides a mixture of the isomeric bromo compounds(122) and (123) which react with potassium thioacetate to give a mixtureof isomers from which (124) may be separated. Solvolysis of thethioester produces the thiol (125) which is alkylated to give (126).Lewis acids convert (126) to the thiopyrano[3,4-b]indole (127). Theester function is converted to amide using methylchloroaluminum amide,the methyl ether cleaved by boron tribromide, and the product phenolO-alkylated with bromoacetic ester to give (130) which is hydrolyzed to(131).

X is halo,

R^(3(a)) is as defined in Scheme I(a) above; and

R is —(CH₂)mR⁵.

Protection of the oxygen by treatment of (132) withtert-butyldimethylsilyl chloride and imidazole in an aprotic polarsolvent such as tetrahydrofuran or methylene chloride accomplishes(133).

Alkylation at the 3-position of the indole (133) is achieved bytreatment with n-butyllithum then zinc chloride at temperatures startingat about 10° C. and warming to room temperature, followed by reactionwith an appropriate haloalkyl ester such as methyl or ethylbromoacetate. The reaction is preferably conducted at room temperaturein an appropriate aprotic polar solvent such as tetrahydrofuran.

Alkylation of the indole-nitrogen can then be achieved by reacting (134)with a suitable alkyl halide in the presence of potassiumbis(trimethylsilyl)amide to prepare (135).

The ester functionality of (135) is converted to a trimethylsilylketeneacetal (136) by treatment with potassium bis(trimethylsilyl)amide andtrimethylsilyl chloride. Treatment of the ketene acetal (136) withbis(chloromethyl)sulfide and zinc bromide in methylene chloride affordsthe cyclized product (137). Conversion to amide (138) can beaccomplished by a Weinreb reaction with methylchloroaluminum amide.Removal of the oxygen protecting group with a fluoride source, such astetrabutylammonium fluoride (TBAF), and concommitant reaction of theresulting anion with, for example, ethyl bromoacetate yields the ester(139). Deprotection of the ester yields the desired acid (140).

R^(3(a)) is as described in Scheme I(a) and

R is as described in Scheme IV(d).

Treatment of the ketene acetal (136) with bis(chloromethyl)ether andzinc bromide in methylene chloride affords the cyclized product (141).Conversion to amide (142) can be accomplished by a Weinreb reaction withmethylchloroaluminum amide. Removal of the oxygen protecting group witha fluoride source, such as tetrabutylammonium fluoride, and concommitantreaction of the resulting anion with ethyl bromoacetate yields the ester(143). Deprotection of the ester yields the desired acid (144).

N-alkylation of commercially available 4-methoxy indole (231) underbasic conditions using an alkyl halide affords the N-alkyl indole (232).Acylation with a suitable acid chloride provides the glyoxalate esterproduct (233) which can be reduced with a variety of hydride reducingagents to give intermediate alcohols (234). Conversion of the alcohol toa suitable leaving group and displacement with sulfur nucleophilesaffords the thioether product (235). Conversion to the acid chloride andspontaneous cyclization affords the thioketone product (236). Cleavageof the ester can be effected under basic conditions to give thecorreponding acid which upon formation of the acid chloride and reactionwith an appropriate amine gives the amide product (237). Cleavage of themethyl ether gives the phenol (238) which can be alkylated under basicconditions using alkyl halides to give the O-alkylated product (239).Cleavage of the ester under basic conditions gives the desired product(240). Alternatively, reduction of the benzylic ketone with a hydridereducing agent and subsequent deoxygenation of the resulting alcoholgives the deoxygenated product (244). Cleavage of the oxyacetic esterproceeds under basic conditions to give the desired oxyacetic acid(242).

Compounds where Z is an aromatic or heterocyclic ring containingnitrogen can be prepared as described in Schemes V(a)-(e), below.

Substituted haloaniline (145) is condensed with N-benzyl-3-piperidone toprovide enamine (146). Ring closure is effected by treatment of (146)with palladium (II) acetate and the resultant product is converted to(147) by treatment with cyanogen bromide. Alkylation of (147) isaccomplished by treatment with the appropriate alkyl bromide usingsodium hydride as base. Hydrolysis of this N-alkylated product withbasic hydrogen peroxide under standard conditions provides (148).Demethylation of (148) is carried out by treatment with boron tribromidein methylene chloride. The resulting phenol (149) is converted by thestandard sequence of O-alkylation with methyl bromoacetate in thepresence of a base, hydrolysis with hydroxide to provide theintermediate salt which is then protonated in aqueous acid to providedesired δ-carboline (150).

X is halo,

R is as defined in Scheme IV(d), and

R^(3(a)) is as defined in Scheme I(a).

Ketene acetal (136), prepared as described in Scheme IV(d), is reactedwith benzyl bis(methoxymethyl)amine in the presence of zinc chloride togive the tetrahydrobeta-carboline (151).

Treatment of (151) with lithium hydroxide, neutralization withhydrochloric acid and subsequent treatment with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and ammoniaprovides the desilyated amide (152) where R²⁰ is hydrogen, which can bealkylated with, for example, ethylbromoacetate to give ester (153).

Alternatively, treatment of (115) with the appropriate Weinreb reagentprovides amide (152) (R²⁰ is t-butyldimethylsilyl) which is desilylatedwith tetra-n-butylammonium fluoride and alkylated with, for example,ethyl bromoacetate to give ester (153). Lithium hydroxide-mediatedhydrolysis gives acid (154), which may be hydrogenated over anappropriate catalyst in the presence of hydrochloride acid to give thetetrahydrobeta-carboline as the hydrochloride salt(155). Compound (155)may in turn be aromatized by refluxing in carbitol with palladium oncarbon to provide beta-carboline (156).

X is halo,

R is as defined in Scheme IV(d); and

R^(3(a)) is as defined in Scheme I(a).

In a one-pot reaction, indole (133) is successively treated with oneequivalent n-butyllithium, carbon dioxide gas, one equivalent oft-butyllithium, and 1-dimethylamino-2-nitroethene to give (157).Nitroalkene (157) is reduced with lithium aluminum hydride to amine(158), which is cyclized with methyl glyoxylate (Ref. 9) in refluxingethanol to give tetrahydrocarboline (159). Alkylation of both nitrogensof (159) leads to intermediate (160), which is treated with theappropriate Weinreb reagent to provide amide (161). Fluoride-assisteddesilylation and alkylation with, for example, ethyl iodoacetate givesester (162), which may be hydrogenated over a suitable catalyst andbase-hydrolyzed to give acid (163). Aromatization of (163) to carboline(164) is achieved by refluxing in carbitol in the presence ofpalladium-on-carbon.

Reference 9

Kelley, T. R.; Schmidt, T. E.; Haggerty, J. G. A convenient preparationof methyl and ethyl glyoxylate, Synthesis, 1972, 544-5.

The commercially available acid (170) is reduced with lithium aluminumhydride, oxidized with pyridinium chlorochromate, and silylated witht-butyldimethylsilyl chloride to give (171). Treatment with sodium azideprovides azide (172), which is reacted with nitromethane and potassiumhydroxide in ethanol, followed by treatment with acetic anhydride andpyridine to give nitroolefin (173). Heating in xylene inducescyclization to produce indole (174). Alkylation with, for example,benzyl iodide and sodium hydride gives (175), which is hydrogenated inthe presence of palladium-on-carbon to give amine (176). Acylation withthe acid chloride of commercially available oxalacetic acid monoethylester gives (177), which is thermally cyclized to lactam (178).Selective reduction of the lactam carbonyl may be accomplished bytreatment with NaBH₂S₃ to provide amine (179).

Protection of amine (179) with di-t-butyl dicarbonate and pyridineproduces (180), which is converted via the appropriate Weinreb reagentto amide (181). Fluoride-assisted desilylation, alkylation with, forexample, ethyl iodoacetate and potassium carbonate, base hydrolysis, andacid hydrolysis produce the tetrahydro-alpha-carboline (182).

Alternatively, amine (179) may be aromatized by refluxing in carbitol orsome other suitable high boiling solvent to give alpha-carboline (183),which is converted via the appropriate Weinreb reagent to amide (184).Fluoride-assisted desilylation, alkylation with ethyl iodoacetate andpotassium carbonate, and base hydrolysis as described above providesalpha-carboline (185).

X is halo

R^(3(a)) is as defined above

Scheme V(e) provides δ-carboline (198) by the indicated sequence ofreactions. N-alkylation of 2-carboethoxyindole (190) followed by astandard two carbon homologation sequence provides 2-(3-propenoicacid)indoles (194). In this sequence, the condensation of aldehyde (193)with malonic acid utilized a mixture of pyridine and piperidine as thebase. After methyl ester formation and hydrogenation (195), ring closure(196) was effected by treatment withbis(2,2,2-trichloroethyl)azodicarboxylate (BTCEAD) followed by zinc inacetic acid. Reduction of the cyclic amide with lithium aluminum hydridefollowed by treatment with trimethylsilylisocyanate provided the urea(197). Conversion to the desired d-carboline (198) was accomplishedunder the usual conditions of demethylation and subsequent alkylationand ester hydrolysis steps.

Reverse indoles, i.e., compounds where B is carbon and D is nitrogen canbe prepared as described in Scheme VI, below.

Aryl hydrazines (200) are condensed with substituted prpionaldehydes toform hydrazones which are cyclized to indoles (201) by treatment withphosphorous trichloride at room temperature (Ref 1). The indoles areN-alkylated on reaction with a base such as sodium hydride and analph-bromo ester to give indoles (202) which are cyclized totetrahydrocarbazoles (203) by Lewis acids (e.g., aluminum chloride) orby radical initiators (e.g., tributyltin hydride). Compounds (203) canbe converted to carbazoles by, for example, refluxing in a solvent suchas carbitol in the presence of Pd/C.

Compounds of formula I wherein A is pyridyl can be prepared as describedin Schemes VII(a)-(b), below.

X is halo and

R is (CH₂)_(m)R⁵.

Commercially available 4-chloroindole (210) is treated with 3equivalents of t-butyllithium followed by carbon dioxide, 1 equivalentof n-butyllithium, 1-dimethylamino-2-nitroethene, and acid to providecarboxylic acid (211), which may be esterified to give (212). Alkylationat the 1-position followed by hydrogenation provides aminoethyl indole(214). Cyclization with phosgene to (215) followed by aromatizationgives carboline (216). Treatment of (216) with the appropriate Weinrebreagent provides amide (217), which may be alkylated with, for example,ethyl bromoacetate and saponified with sodium hydroxide to give thecarboline (218).

R3(a) is as defined in Scheme I(a),

X is halo, and

R is (CH₂)mR⁵.

The 1,3-dione structures (228) are either commercially available orreadily prepared by known techniques from commercially availablestarting materials. Preparation of the aniline derivatives (220) (X=Cl,Br, or I) are accomplished by reducing an appropriately substitutedbenzoic acid derivative to the corresponding aniline by treatment with areducing agent such as SnCl₂ in hydrochloric acid in an inert solventsuch as ethanol or by hydrogenation using hydrogen gas and sulfidedplatinum or carbon or palladium on carbon. The amino group of (228) isprotected with an appropriate protecting group, such as the,carboethoxyl, benzyl, CBZ (benzyloxycarbonyl) or BOC(tert-butoxycarbonyl) protecting group, and the like.

The dione (228) and aniline derivative (220) are condensed according tothe general procedure of Chen, et al., (Ref 10) or Yang, et al., (Ref11), with or without a noninterfering solvent, such as methanol,toluene, or methylene chloride, with or without an acid, such asp-toluenesulfonic acid or trifluoroacetic acid, with or withoutN-chlorosuccinimide and dimethyl sulfide, to afford the coupled product(221).

Compound (221) is cyclized under basic conditions with a copper (I) saltin an inert solvent according to the general procedure of Yang, et al.,(Ref 8). The derivative (221) is treated with a base, such as sodiumhydride, in an inert solvent, such as HMPA, at a temperature between 0and 25° C.. A copper (I) salt, such as copper (I) iodide, is added andthe resultant mixture stirred at a temperature between 25 and 150° C.for 1 to 48 hours to afford compound (222).

Compound (221) may also be cyclized according to the general procedureof Chen, et al., (Ref 10). The derivative (221) is treated with a base,such as sodium bicarbonate, and a palladium catalyst, such as Pd(PPh₃)₄,in an inert solvent, such as HMPA, at a temperature between 25 and 150°C. to afford compound (222).

In a preferred method, intermediate (171) is treated with a transitionmetal catalyst, such as Pd(OAc)₂(O-tol)₃P in the presence of a base suchas triethylamine using a cosolvent of DMF/acetonitrile to prepare (222).

Compound (222) is N-alkylated with an appropriately substituted benzylhalide in the presence of a base, such as sodium hydride or potassiumcarbonate, in a noninterfering solvent, such as dimethylformamide ordimethylsulfoxide to afford ketone (223). In a two step, one pot process(222) is aromatized by treatment with acetic acid and palladium oncarbon in a noninterfering solvent, such as carbitol or cymene, followedby treatment with hydrogen gas and palladium on carbon to cleave thenitrogen protecting group and produce the phenolic derivative (224).

The ester (224) is converted to the corresponding amide (225) understandard conditions with ammonia (preferably) or an ammonium salt, suchas ammonium acetate, in an inert solvent, such as water or alcohol,preferably methanol, or with MeClAlNH₂ in an inert solvent, such astoluene, at a temperature between 0 to 110° C. Alkylation of thephenolic oxygen of compound 38 with an appropriate haloester, such asmethyl bromoacetate, in the presence of a base, such as cesiumcarbonate, potassium or sodium carbonate, in an inert solvent, such asdimethylformamide or dimethylsulfoxide affords the ester-amide (226).Other haloesters, such as ethyl bromoacetate, propyl bromoacetate, butylbromoacetate, and the like can also be used to prepare the correspondingesters.

Saponification of compound (226), with lithium hydroxide in an inertsolvent, such as methanol-water, affords (227). The intermediate andfinal products may isolated and purified by conventional techniques suchas chromatography or recrystallization. Regioisomeric products andintermediates can be separated by standard methods, such as,recrystallization or chromatography.

References

10) L.-C. Chen et al., Synthesis 385 (1995)

11) S.-C. Yang et al., Heterocycles, 32, 2399 (1991)

h) Pyrazole sPLA₂ Inhibitors

The method of the invention may be practiced using pyrazole sPLA2inhibitors, which are described (together with the method of making) inU.S. patent application Ser. No. 08/984261, filed Dec. 3, 1997, theentire disclosure of which is incorporated herein by reference. Suitablepyrazole compounds are represented by formula (Ih)

wherein:

R¹ is phenyl, isoquinolin-3-yl, pyrazinyl, pyridin-2-yl, pyridin-2-ylsubstituted at the 4-position with —(C₁-C₄)alkyl, (C₁-C₄)alkoxyl, —CN or—(CH₂)_(n)CONH₂ where n is 0-2;

R² is phenyl; phenyl substituted with 1 to 3 substituents selected fromthe group consisting of —(C₁-C₄)alkyl, —CN, halo, —NO₂, CO₂(C₁-C₄)alkyland —CF₃; naphthyl; thiophene or thiophene substituted with 1 to 3 halogroups;

R³ is hydrogen; phenyl; phenyl(C₂-C₆)alkenyl; pyridyl; naphthyl;quinolinyl; (C₁-C₄)alkylthiazolyl; phenyl substituted with 1 to 2substituents selected from the group consisting of —(C₁-C₄)alkyl, —CN,—CONH₂, —NO₂, —CF₃, halo, (C₁-C₄)alkoxy, CO₂(C₁-C₄)alkyl, phenoxy andSR⁴ where R⁴ is —(C₁-C₄)alkyl or halophenyl; phenyl substituted with onesubstituent selected from the group consisting of

—O(CH₂)_(p)R⁵ where p is 1 to 3 and R⁵ is —CN, —CO₂H, —CONH₂, ortetrazolyl, phenyl and

—OR⁶ where R⁶ is cyclopentyl, cyclohexenyl, or phenyl substituted withhalo or (C₁-C₄)alkoxy;

or phenyl substituted with two substituents which, when taken togetherwith the phenyl ring to which they are attached form a methylenedioxyring; and

m is 1 to 5;

or a pharmaceutically acceptable salt thereof.

Particularly preferred are pyrazole type sPLA₂ inhibitors as follows:

A pyrazole compound of formula (I), supra, wherein:

R¹ is pyridine-2-yl or pyridine-2-yl substituted at the 4-position with—(C₁-C₄)alkyl, (C₁-C₄)alkoxy, —CN or —(CH₂)_(n)CONH₂ where n is 0-2;

R² is phenyl substituted with 1 to 3 substituents selected from thegroup consisting of —(C₁-C₄)alkyl, —CN, halo, —NO₂, CO₂(C₁-C₄)alkyl and—CF₃; and

R3 is phenyl; phenyl(C₂-C₆)alkenyl; phenyl substituted with 1 or 2substituents selected from the group consisting of —(C₁-C₄)alkyl, —CN,—CONH₂, —NO₂, —CF₃, halo, (C₁-C₄)alkoxy, CO₂(C₁-C₄)alkyl, phenoxy andSR₄ where R⁴ is —(C₁-C₄)alkyl or halo phenyl;

phenyl substituted with one substituent selected from the groupconsisting of —O(CH₂)pR⁵ where p is 1 to 3 and R⁵ is —CN, —CO₂H, —CONH₂or tetrazolyl, phenyl and —OR⁶ where R⁶ is cyclopentyl, cyclohexenyl orphenyl substituted with halo or (C₁-C₄)alkoxy;

or phenyl substituted with two substituents which when taken togetherwith the phenyl ring to which they are attached form a methylenedioxyring.

Specific suitable pyrazole type sPLA₂ inhibitors useful in the method ofthe invention are as follows:

Compounds selected from the group consisting of3-(2-chloro-6-methylphenylsulfonylamino)-4-(2-(4-acetamido)pyridyl)-5-(3-(4-fluorophenoxy)benzylthio)-(1H)-pyrazoleand3-(2,6-dichlorophenylsulfonylamino)-4-(2-(4-acetamido)pyridyl)-5-(3-(4-fluorophenoxy)benzylthio)-(1H)-pyrazole.

The pyrazole compounds of formula Ih are prepared as described in SchemeI below.

L is a leaving group.

In an aprotic polar solvent, such as tetrahydrofuran, an acetonitrilecompound (1) is deprotonated by treatment with an excess of a strongbase, such as sodium hydride, preferably under an inert gas, such asnitrogen. The deprotonated intermediate is treated with carbon disulfideand then alkylated twice with an appropriately substituted alkyl halide(2) of the formula R³(CH₂)_(m)L, where L is a leaving group, preferablybromine, and R³ and m are as defined above, to prepare intermediatecompound (3). The reaction is conducted at ambient temperatures and issubstantially complete in 1 to 24 hours.

Cyclization to form the amino substituted pyrazole (4) is achieved byreacting intermediate (3) with hydrazine at room temperature for fromabout 1 to 24 hours.

Selective sulfonylation of the amino group of intermediate (4) can beaccomplished by treatment with a sulfonyl chloride (5) of the formulaR²SO₂Cl, where R² is as defined above, to prepare product (6). Thereaction is preferably conducted in a solvent, such as pyridine, atambient temperature for a period of time of from 1 to 24 hours.Preparation of 2,6-dimethylphenylsulfonyl chloride can be accomplishedas described in J. Org. Chem. 25, 1996 (1960). All other sulfonylchlorides are commercially available.

i) Phenyl glyoxamide sPLA₂ inhibitors (and the method of making them)are described in U.S. patent application Ser. No. 08/979446, filed Nov.24, 1997 (titled, Phenyl Glyoxamides as sPLA₂ Inhibitors), the entiredisclosure of which is incorporated herein by reference.

The method of the invention is for treatment of a mammal, including ahuman, afflicted with a non-rheumatoid arthritis, said method comprisingadministering to said human a therapeutically effective amount a phenylglyoxamide type sPLA₂ inhibitors useful in the method of the inventionare as follows:

A compound of the formula (Ii)

 wherein:

X is —O— or —(CH₂)_(m)—, where m is 0 or 1;

Y is —CO₂—, —PO₃—, —SO₃—;

R is independently —H or —(C₁-C₄)alkyl;

R¹ and R² are each independently —H, halo or —(C₁-C₄)alkyl;

R³ and R⁴ are each independently —H, —(C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, halo, phenyl or phenyl substituted with halo;

n is 1-8; and

p is 1 when Y is —CO₂— or —SO₃— and 1 or 2 when Y is —PO₃—;

 or a pharmaceutically acceptable salt thereof.

A specific suitable phenyl glyoxamide type sPLA₂ inhibitors is2-(4-carboxybut-1-yl-oxy)-4-(3-phenylphenoxy)phenylglyoxamide.

These phenyl glyoxylamide compounds useful in the method of theinvention are prepared as follows:

Compounds where R¹, R², R³ and R⁴ are H, and X, Y and n and p are asdefined above can be prepared according to the following Scheme I.

R′ is —(C₁-C₄)alkyl

Reflux of (1) with oxalyl chloride in an alkyl halide solvent, such aschloroform, using 4-N,N′ dimethylamino pyridine as a catalyst achievesintermediate (2).

Under Friedel-Crafts conditions, using a suitable Lewis-acid catalystsuch as aluminum chloride, compound (2) is internally cyclized to formcompound (3). The reaction is preferably conducted at temperatures fromabout 0° C. to room temperature and allowed to proceed for about 24hours.

Aminolysis of (3) to amide (4) can be achieved by treatment withconcentrated ammonium hydroxide.

Alkylation of the hydroxyl of compound (4) can be readily achieved bytreatment with an appropriate alkylating agent, such as Br(CH₂)_(n)Y,where Y is —CO₂R, —PO₃R₂ or SO₃R and R is —(C₁-C₄)alkyl, to formintermediate (5). The reaction is preferably conducted in an aproticpolar solvent, such as dimethyl formamide, in the presence of potassiumcarbonate and a suitable catalyst, such as potassium iodide.

Conversion of (5) to the carboxylic or sulfonic acid or acid salt (6)may be achieved by treatment with an appropriate base, such as aqueoussodium hydroxide, in a polar protic solvent, such as methanol.

When n is 2, a bromoacetal must be employed as an alkylating agent toachieve the carboxylic acid (6). The alkylated moiety (5) is thenconverted to the acid (6) by oxidizing with sodium dichromatate inaqueous conditions.

When Y is —PO₃—, conversion to the acid (6), is preferably conducted inan alkyl halide solvent, such as methylene chloride, using adealkylating agent, such as trimethylsilyl bromide, and an excess ofpotassium carbonate, followed by treatment with methanol.

When R¹, R², R³ or R⁴ are other than hydrogen, the preparation proceedsas described in Scheme II on the following page.

R′ is as defined in Scheme I.

An appropriately R¹, R² substituted phenol (7) is converted to lactone(8) following the procedures described in Scheme I, steps (a-b) above.

Conversion to the intermediate (9) is accomplished by reacting (2a) withan aqueous acid, such as hydrochloric acid which affords removal ofaluminum chloride from the reaction. Acid (9) is converted to thecorresponding acid chloride using oxalyl chloride with dimethylformamide as a catalyst. The acid chloride is recyclized to the lactone(10) on removal of the solvent, preferably under vacuum. The lactone(10) is converted to the glyoxamide (11) by atreatment with an excess ofammonia as described in Scheme I, step (c), above.

Alkylation of (11) to prepare the ester (12), followed by conversion tothe acid is accomplished according to the procedure outlined in SchemeI, steps (d) and (e).

Alternately, conversion of (10) to (12) can be accomplished in a one-potprocedure by treating the lactone (10) with sodium amide in an aproticpolar solvent, such as dimethylformamide, preferably at temperatures offrom about 0° C. to 20° C., followed by alkylation with an appropriatealkyl halide.

j) Pyrrole sPLA₂ inhibitors and methods of making them are disclosed inU.S. patent applicaton Ser. No. 08/985518 filed Dec. 5, 1997 (titled,“Pyrroles as sPLA₂ Inhibitors”), the entire disclosure of which isincorporated herein by reference.

The method of the invention is for treatment of a mammal, including ahuman, afflicted with a non-rheumatoid arthritis, said method comprisingadministering to said human a therapeutically effective amount a pyrrolesPLA₂ inhibitors useful in the method of the invention as follows:

A compound of the formula (Ij)

R¹is hydrogen, (C₁-C₄)alkyl, phenyl or phenyl substituted with one ortwo substituents selected from the group consisting of —(C₁-C₄)alkyl,(C₁-C₄)alkoxy, phenyl(C₁-C₄)alkyl, (C₁-C₄)alkylthio, halo and phenyl;

R² is hydrogen, —(C₁-C₄)alkyl, halo, (C₁-C₄)alkoxy or (C₁-C₄)alkylthio;

R³ and R⁴ are each hydrogen or when taken together are ═O;

R⁵ is —NH₂ or —NHNH₂;

R⁶ and R⁷ are each hydrogen or when one of R⁶ and R⁷ is hydrogen, theother is —(C₁-C₄)alkyl, —(CH₂)_(n)R¹⁰ where R¹⁰ is —CO₂R¹¹, —PO₃(R¹¹)₂,—PO₄(R¹¹)₂ or —SO₃R¹¹ where R¹¹ is independently hydrogen or—(C₁-C₄)alkyl and n is 0 to 4; or R⁶ and R⁷, taken together, are ═O or═S;

X is R⁸(C₁-C₆)alkyl; R⁸(C₂-C₆)alkenyl or phenyl substituted at the orthoposition with R⁸ where R⁸ is (CH₂)_(n)R¹⁰ where R¹⁰ is —CO₂R¹¹,—PO₃(R¹¹)₂, —PO₄(R¹¹) or —SO₃R¹¹, R¹¹ and n is 1 to 4 as defined above,and additionally substituted with one or two substituents selected fromthe group consisting of hydrogen, —(C₁-C₄)alkyl, halo, (C₁-C₄)alkoxy, ortwo substituents which, when taken together with the phenyl ring towhich they are attached, form a naphthyl group; and

R⁹ is hydrogen or methyl or ethyl;

 or a pharmaceutically acceptable salt thereof.

Preferred pyrrole sPLA₂ inhibitors useful in the method of the inventionare compounds of formula Ij wherein;

R¹ is phenyl;

R² is methyl or ethyl;

R⁵ is —NH₂;

R⁶ and R⁷ are each hydrogen;

X is R⁸(C₁-C₆)alkyl or phenyl substituted at the ortho position with R⁸where

R⁸ is —CO₂R¹¹; and

R⁹ is methyl or ethyl.

A specific suitable pyrrole sPLA₂ inhibitors useful in the method of theinvention is2-[1-benzyl-2,5-dimethyl-4-(2-carboxyphenylmethyl)pyrrol-3-yl]glyoxamide.

The pyrrole compounds are prepared as follows:

Compounds of formula I where R⁵ is —NH₂ can be prepared as shown inScheme I, below.

An appropriately substituted gamma-diketone (1) is reacted with analkylamine of the formula NHCH₂R¹ to give pyrrole (2). UnderFriedel-Crafts conditions, using a suitable Lewis-acid catalyst such asstannic chloride, aluminum chloride, or titanium tetrachloride(preferably stannic chloride) pyrrole (2) is ring alkylated with analkyl or arylalkyl halide compound of the formula ZCR⁶R⁷X where Z is asuitable halogen and R⁸ of X is a protected acid or ester. The reactionis preferably conducted in a halogenated hydrocarbon solvent, such asdichloromethane, at ambient temperatures and allowed to proceed for fromabout 1 to about 24 hours.

Intermediate (3) is converted to (4) by sequential treatment with oxalylchloride followed by ammonia. Selective reduction of (4) is accomplishedin a two step process. In a hydride reduction using, for example, sodiumborohydride, the hydroxy intermediate (5) is prepared which can befurther reduced using either catalytic or hydride reduction (preferablypalladium on carbon) to prepare (6). Deprotection of R⁸ to the acid maybe readily achieved by conventional techniques. For example, when analkyl ester is used as a protecting group, deprotection can beaccomplished by treatment with a base, such as sodium hydroxide.

k) Naphthyl glyoxamide sPLA₂ inhibitors and methods of making them aredescribed in U.S. patent application Ser. No. 09/091079, filed Dec. 9,1966 (titled, “Naphthyl Glyoxamides as sPLA2 Inhibitors”), the entiredisclosure of which is incorporated herein by reference.

The method of the invention is for treatment of a mammal, including ahuman, afflicted with a non-rheumatoid arthritis, said method comprisingadministering to said human a therapeutically effective amount anaphthyl glyoxamide sPLA₂ inhibitors useful in the method of theinvention are as follows:

A naphthyl glyoxamide compound or a pharmaceutically acceptable salt,solvate or prodrug derivative thereof; wherein said compound isrepresented by the formula Ik

 wherein:

R¹ and R² are each independently hydrogen or a non-interferingsubstituent with the proviso that at least one of R¹ or R² must behydrogen;

X is —CH₂— or —O—; and

Y is (CH₂)_(n)Z where n is a number from 1-3 and Z is an acid groupselected from the group consisting of CO₂H, —SO₃H or —PO(OH)₂.

A specific suitable naphthyl glyoxamide sPLA₂ inhibitors useful in themethod of the invention has the following structural formula:

The naphthyl glyoxamide compounds are prepared as follows:

Compounds of formula I where X is oxygen can be prepared by thefollowing reaction Scheme I.

In the above depicted reaction scheme, the 1,5-dihydroxy napthalenestarting material (1) is dispersed in water and then treated with 2equivalents of potassium hydroxide. The resultant solution is chilled inan ice bath and one equivalent of a strong mineral acid, such ashydrochloric acid, is added to produce the potassium salt (2).

Alkylation of the radical (2) can then be accomplished by treatment witha methylating agent such as dimethyl sulfate to prepare the ether (3).

Preparation of (4) is achieved by reacting the ether (3) with anappropriately substituted phenol in an Ullman-type reaction usingpotassium carbonate and cupric oxide.

De-methylation of (4) can be accomplished by treating (4) with a 40%HBr/HOAC solution at reflux in a protic polar solvent such as aceticacid, to prepare (5).

Reflux of compound (5) with oxalyl chloride and 4-demethylaminopyridine, in an alkylhalide solvent such as methylene chloride, preparesthe oxalyl chloride (6).

Internal cyclization of (6) can be achieved under Friedel-Craftscondition using aluminum chloride or other similar metal halide as thecatalyst. The reaction can be conveniently conducted in an alkyl halidesolvent, such as 1,2-dichloro ethane.

Alkylation and hydrolysis of the cyclized compound (7) can be achievedby reacting (7) with an alkaliamide base, such as sodium amide, followedby treatment with an alkylating agent, such as methyl bromoacetate,using potassium iodide as a catalyst.

Finally, the acid (9) is achieved by treating the ester (8) with analkali base, such as aqueous sodium hydroxide, followed by treatmentwith a dilute aqueous mineral acid such as hydrochloric acid The acidcompound (9) is then extracted with an organic solvent such as ethylacetate.

The final product (9) can be purified using standard recrystallizationprocedures in a suitable organic solvent such as methylenechloride/hexane.

Compounds of formula I where X is methylene can be prepared as shown inthe following Scheme II

Using an appropriately substituted phenyl bromide, a Grignard reagent isprepared. The phenyl Grignard is then reacted with 4-methoxynaphthylnitrile and the resultant compound is hydrolyzed with a diluteacid such as hydrochloric acid to form the benzoyl naphthylene compound(1a ).

Reduction of (1a) to form compound (2a) is accomplished by treatmentwith a reducing agent such as sodium borohydride. The reaction isconducted in a solvent-catalyst such as trifluoroacetic acid andinitiated in an ice bath which is allowed to warm to room temperature asthe reaction proceeds.

The desired naphthyl glyoxamide may then be prepared from (2a) accordingto the procedure in Scheme I starting with the chloromethylation step.

It will be readily appreciated by a person skilled in the art that thesubstituted benzyl bromide, substituted phenol and substitutednaphthylnitrile compounds of Schemes I and II are either commerciallyavailable or can be readily prepared by known techniques fromcommercially available starting materials.

1) Phenyl acetamide sPLA₂ inhibitors and methods of making them aredisclosed in U.S. patent application Ser. No. 08/976858, filed Nov. 24,1997 (titled, “Phenyl Acetamides as sPLA₂ Inhibitors”), the entiredisclosure of which is incorporated herein by reference.

The method of the invention is for treatment of a mammal, including ahuman, afflicted with a non-rheumatoid arthritis, said method comprisingadministering to said human a therapeutically effective amount of aphenyl acetamide sPLA₂ inhibitor represented by formula (I1) as follows:

wherein:

R¹ is —H or —O(CH₂)_(n)Z;

R² is —H or —OH;

R³ and R⁴ are each independently —H, halo or —(C₁-C₄)alkyl;

One of R⁵ and R⁶ is —YR⁷ and the other is —H, where Y is —O— or —CH₂—and R⁷ is phenyl or phenyl substituted with one or two substituentsselected from the group consisting of halo, —(C₁-C₄)alkyl,(C₁-C₄)alkoxy, phenyl or phenyl substituted with one or two halo groups;

Z is —CO₂R, —PO₃R₂ or —SO₃R where R is —H or —(C₁-C₄)alkyl; and

n is 1-8;

or a pharmaceutically acceptable salt, racemate or optical isomerthereof;

provided that when R⁶ is YR⁷, R¹ is hydrogen; and

when R¹, R², R³, R⁴ and R⁶ are hydrogen and R⁵ is YR⁷ where Y is —O—, R⁷cannot be phenyl; and

when R¹, R², R³, R⁴ and R⁶ are hydrogen, R⁵ is YR⁷ where Y is CH₂, R⁷cannot be phenyl substituted with one methoxy or two chloro groups.

Preferred suitable phenyl acetamide sPLA₂ inhibitors useful in themethod of the invention are as follows:

Compounds of formula I wherein R², R³ and R⁴ is H, Y is oxygen or CH₂,R⁷ is phenyl or phenyl substituted at the meta position with one or twosubstituents selected from halo, —(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenyl orphenyl substituted with halo and n is 4-5.

A specific suitable phenyl acetamide sPLA₂ inhibitors useful in themethod of the invention is2-(4-carboxybutoxy)-4-(3-phenylphenoxy)phenylacetamide.

The phenyl acetimde compounds are prepared as follows:

Compounds of formula I where R¹ and R² are H, R⁵ or R⁶ are YR⁷ where R⁷is phenyl or substituted phenyl and Y is oxygen can be prepared asillustrated in Scheme I(a), below.

X is halo;

R⁸ and R⁹ are each independently —H, halo, —(C₁-C₄) alkyl, (C₁-C₄)alkoxy, phenyl or phenyl substituted with one or two halo groups; and

PG is a carboxyl protecting group.

An appropriately substituted carboxy-protected halophenyl compound (1),where the halogen is preferably bromine, is coupled with anappropriately substituted phenol (2) under modified Ullmann conditions,by refluxing with potassium carbonate and cupric oxide in an aproticpolar solvent, such as pyridine, under an inert gas such as argon. Thereaction is substantially complete in 1-24 hours.

Intermediate (3) is deprotected by treatment with a base such as aqueouspotassium hydroxide using a solvent, such as diethylene glycol. Thereaction, preferably conducted at about 100°-150° C., is substantiallycomplete in 1-24 hours.

Conversion to the amide (5) can then be readily achieved by treatmentfirst with oxalyl chloride in an alkyl halide solvent, such as methylenechloride, using dimethylformamide as a catalyst, at temperatures of fromabout 0° C. to ambient temperature, followed by treatment with an excessof ammonia gas, again in an alkyl halide solvent.

Alternately, compounds of formula I can be prepared according to theprocedure of Scheme I(b), below.

The substituted phenol (2) is coupled with an appropriately substitutedbenzyl halide (6) as described in Scheme I(a), step a, above, to prepare(7).

Halogenation of (7) is achieved using a halogenating agent, such asN-bromosuccinimide and a catalyst, such as 2,2′azobisisobutyronitrile,in an alkyl halide solvent, such as chloroform, to prepare (8).

Treatment of (8) with sodium cyanide in an aprotic polar solvent, suchas dimethyl formamide produces the nitrile (9) which can then be readilyconverted to the amide (10) by treatment with an aqueous acid, such ashydrochloric acid.

R⁸ and R⁹ are as shown in Scheme I(a),

X is halo.

In another procedure, compounds of formula I where R¹, R², R³ and R⁴ arehydrogen, Y is —O— or —CH₂— and R⁷ is phenyl can be prepared asportrayed in Scheme II on the following page.

X is a halogen.

An appropriate diphenyl compound (11) is treated with paraformaldehydeand a halogenating agent, such as 40% hydrogen bromide in acetic acid.Two positional isomers result with the X substituent at either the metaor para position of the phenyl ring to which it is attached.

Displacement of the halogen to prepare the nitrile isomers (13) can beachieved by treatment of (12) with sodium cyanide in dimethylformamideas described in Scheme I(b), step (c), above. The isomers can then bereadily separated by conventional chromatographic techniques and eachisomer may be converted to its respective amide (14) by treatment withhydrogen peroxide and potassium carbonate in an aprotic polar solvent,such as dimethylsulfoxide.

Compounds where R¹ is —O(CH₂)_(n)Z can be prepared as illustrated inScheme III, below.

R is —(C₁-C₄)alkyl and

p=1 or 2.

Intermediate (16) is prepared by refluxing an appropriately substituteddiphenyl compound (15) with oxalyl chloride in an alkyl halide solvent,such as chloroform. Preferably the reaction is catalyzed with4,4-N-dimethylaminopyridine.

Cyclization to the lactone (17) can be achieved under Friedel-Craftsconditions using a suitable metal halide, such as aluminum chloride, asthe catalyst. Conversion to the glyoxamide (18) can be achieved byaminolysis of the lactone ring using concentrated ammonium hydroxide.

Alkylation of the hydroxy group to prepare the desired alkyl-linkedester (19) occurs by treatment of (18) with an appropriate alkylatingagent, such as (X)(CH₂)_(n)B where B is CO₂PG, —PO₃PG or —SO₃PG, X ishalo and PG is an acid protecting group, preferably methyl.

Partial reduction of the carbonyl in the glyoxamide (19) is achieved bytreatment with a suitable reducing agent, such as sodium borohydride inmethanol, preferably at temperatures of from 0°-20° C., to prepare theintermediate (20). The desired acid or acid salt (21) can beaccomplished by treatment with a suitable base, such as sodiumhydroxide.

Further reduction of intermediate (20) can be achieved by treatment withtriethylsilane in a strong acid, such as trifluroacetic acid, under aninert gas, such as argon, to prepare (22) followed, again, by conversionto the acid or salt (23) with a strong base.

m) Naphthyl acetamide sPLA₂ inhibitors and the method of making them aredescribed in U.S. patent application Ser. No. 09/091077, filed Dec. 9,1996 (titled, “Benzyl naphthalene sPLA₂ Inhibitors”), the entiredisclosure of which is incorporated herein by reference.

The method of the invention is for treatment of a mammal, including ahuman, afflicted with a non-rheumatoid arthritis, said method comprisingadministering to said human a therapeutically effective a naphthylacetamide sPLA₂ inhibitor represented by formula (Im) as follows:

wherein:

R¹ and R² are each independently hydrogen or a non-interferingsubstituent with the proviso that at least one of R¹ and R² must behydrogen;

R³ is hydrogen,

 where n is from 2 to 4 and Y is —CO₂H, —PO₃H₂ or SO₃H; and

X is —O— or —CH₂—.

Compounds where X is oxygen can be prepared by the following Scheme I.

In the first step of the above reaction scheme, an appropriatelysubstituted 1-bromo-4-methylnapthalene and an appropriately substitutedphenol are dissolved in an aprotic polar solvent such as pyridine. Themixture is treated with an excess of potassium carbonate and an excessof copper-bronze and refluxed under a nitrogen blanket to produce (1).

Bromination of compound (1) to produce (2) is accomplished by refluxing(1) with a brominating agent, such as N-bromosuccinamide, in a non-polaralkyl halide solvent, such as carbon tetrachloride, using2,2-azobisisobutyronitrile as a catalyst.

Treatment of (2) with sodium cyanide produces (3). This reaction is bestconducted in an aprotic polar solvent, such as dimethyl sulfoxide(DMSO), while heating to a temperature of about 60° C.

Hydrolysis of the cyano compound (3) to produce the acid (4) isaccomplished in two steps. Using a polar protic solvent, such asdiethylene glycol as a cosolvent, the cyano compound (3) is treated withan alkali metal base, such as potassium hydroxide, and the mixture isheated to about 90-95° C. The resultant product is then reacted with astrong mineral acid such as hydrochloric acid.

Conversion of (4) to the desired naphthyl acetamide compound (5) isaccomplished by another two-step process. First, the acid (4) isdissolved in an alkyl halide solvent such as methylene chloride. Theacid/alkyl halide solution is chilled in an ice bath then treated withoxalyl chloride, using dimethylformamide (DMF) as a catalyst, to producethe acid chloride. The solution is allowed to warm to room temperatureand then treated with ammonia gas at room temperature to produce (5).

The desired product (5) can be purified using standard recrystallizationprocedures in a suitable organic solvent, preferably methylenechloride/hexane.

Compounds where X is methylene can be prepared by the following SchemeII

Compound (1a) is prepared by a grignard reaction. The Grignard reagentstarting material is prepared by reacting an appropriately substitutedphenyl bromide with magnesium and ether. The reagent is then reactedwith an appropriately substituted naphthyl nitrile and the resultantcompound is hydrolyzed with an aqueous acid such as hydrochloric acid toform the benzoyl napthyl (1a).

Reduction of (1a) is accomplished by treatment with a molar excess of areducing agent such as sodium borohydride. The reaction is initiated inan ice bath using a solvent-catalyst such as trifluoroacetic acid andthen allowed to warm to room temperature as the reduction proceeds.

Chloromethylation of (2a) is achieved by treatment with an excess offormaldehyde and concentrated hydrochloric acid in a polar acidicsolvent such as an acetic/phosphoric acid mixture. The reaction is bestconducted at a temperature of about 90° C.

The nitrile 4(a) is prepared by a nucleophilic displacement of thechloride compound (3a) with cyanide. The reaction is conducted byrefluxing (3a) with a slight molar excess in an aprotic polar solvent ofsodium cyanide such as dimethylformamide (DMF) for about five hours,then allowing the reaction to continues while it cools to roomtemperature.

The desired naphthylamide (5a) is then prepared from the nitrile (4a) ina three-step process. To a solution of nitrile (4a), dissolved in anaprotic polar solvent such as DMSO, potassium carbonate is added to makethe nitrile solution slightly basic. Hydrolysis of the nitrile is thenachieved by treatment with an aqueous hydrogen peroxide solution.Crystallization of the naphthyl acetamide may be accomplished by addingwater to the peroxide solution.

Compounds where R³ is other than hydrogen can be readily prepared byusing a 1-bromo-4-methyl-napthalene with a protected phenol, such as amethoxy group, on the 6-position of the napthalene ring as a startingmaterial. The process is conducted, as described above, to preparecompounds (1)-(3). Acid hydrolysis of the cyano group (3) anddeprotection of the protected phenol can be accomplished by treating (3)with a 40% hydrogen bromide solution in acetic acid. The deprotectedphenol can then be reacted to prepare the appropriate substituent at the6-position of the napthyl ring. For example, preparation of compoundswhere R³ is —O(CH₂)_(n)COOH can be achieved by alkyalting the phenolwith an appropriate alkyl halide followed by conversion to the acid bytreatment with a base such as aqueous sodium hydroxide followed bydilute hydrochloric acid .

Formulations Suitable for Use in the Method of the Invention

The sPLA₂ inhibitors used in the method of the invention may beadministered to treat non-rheumatoid arthritis by any means thatproduces contact of the active agent with the agent's site of action inthe body of a mammal. They can be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either asindividual therapeutic agents or in a combination of therapeutic agents.The sPLA₂ inhibitors can be administered alone, but are generallyadministered with a pharmaceutical carrier selected on the basis of thechosen route of administration and standard pharmaceutical practice.

Suitable formulations are those comprising a therapeutically effectiveamount of sPLA₂ inhibitor together with a pharmaceutically acceptablediluent or carrier, the composition being adapted for the particularroute of administration chosen. By “pharmaceutically acceptable” it ismeant the carrier, diluent or excipient must be compatible with thesPLA₂ inhibitor (“active compound”) in the formulation and notdeleterious to the subject being treated.

For the pharmaceutical formulations any suitable carrier known in theart can be used. In such a formulation, the carrier may be a solid,liquid, or mixture of a solid and a liquid. A solid carrier can be oneor more substances which may also act as flavoring agents, lubricants,solubilisers, suspending agents, binders, tablet disintegrating agentsand encapsulating material.

Tablets for oral administration may contain suitable excipients such ascalcium carbonate, sodium carbonate, lactose, calcium phosphate,together with disintegrating agents, such as maize, starch, or alginicacid, and/or binding agents, for example, gelatin or acacia, andlubricating agents such as magnesium stearate, stearic acid, or talc. Intablets the sPLA₂ inhibitor is mixed with a carrier having the necessarybinding properties in suitable proportions and compacted in the shapeand size desired. The powders and tablets preferably contain from about1 to about 99 weight percent of the sPLA₂ inhibitor.

Sterile liquid form formulations include suspensions, emulsions, syrupsand elixirs. The active compound can be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, saline,dextrose solution, sterile organic solvent or a mixture of both.

The active compound can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms. It can also beadministered by inhalation in the form of a nasal spray or lung inhaler.It can also be administered topically as an ointment, cream, gel, paste,lotion, solution, spray, aerosol, liposome, or patch. Dosage forms usedto administer the active compound usually contain suitable carriers,diluents, preservatives, or other excipients, as described inRemington's Pharmaceutical Sciences, Mack Publishing Company, a standardreference text in the field.

Gelatin capsules may be prepared containing the active compound andpowdered carriers, such as lactose, sucrose, mannitol, starch, cellulosederivatives, magnesium stearate, stearic acid, and the like. Similardiluents can be used to make compressed tablets and powders. Bothtablets and capsules can be manufactured as sustained release productsto provide for continuous release of medication over a period of hours.Compressed tablets can be sugar coated or film coated to mask anyunpleasant taste and protect the tablet from the atmosphere, or entericcoated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

For parenteral solutions, water, a suitable oil, saline, aqueousdextrose (glucose), and related sugar solutions and glycols such aspropylene glycol or polyethylene glycols are suitable carriers forparenteral solutions. Solutions for parenteral administration containthe active compound, suitable stabilizing agents, and if necessary,buffer substances. Anti-oxidizing agents such as sodium bisulfite,sodium sulfite, or ascorbic acid either alone or combined are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Topical ointments, creams, gels, and pastes contain with the activecompound diluents such as waxes, paraffins, starch, polyethylene glycol,silicones, bentonites, silicic acid, animal and vegetable fats, talc andzinc oxide or mixtures of these or other diluents.

Topical solutions and emulsions can, for example, contain with theactive compound, customary diluents (with the exclusion of solventshaving a molecular weight below 200 except in the presence of asurface-active agent), such as solvents, dissolving agents andemulsifiers; specific examples are water, ethanol, 2-propanol, ethylcarbonate, benzyl alcohol, propylene glycol, oils, glycerol, and fattyacid esters of sorbitol or mixtures thereof. Compositions for topicaldosing may also contain preservatives or anti-oxidizing agents.

Powders and sprays can contain along with the active compound, the usualdiluents, such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicate, and polyamide powders or mixtures of these materials.Aerosol sprays can contain the usual propellants. Liposomes can be madefrom such materials as animal or vegetable fats which will form lipidbilayers in which the active compound can be incorporated.

Formulations containing compounds of the invention may be administeredthrough the skin by an appliance such as a transdermal patch. Patchescan be made of a matrix such as polyacrylamide and a semipermeablemembrane made from a suitable polymer to control the rate at which thematerial is delivered to the skin. Other suitable transdermal patchformulations and configurations are described in U.S. Pat. Nos.5,296,222 and 5,271,940, the disclosures of which are incorporatedherein by reference. Lipophilic prodrug derivatives of the sPLA₂inhibitors are particularly well suited for transdermal absorptionadministration and delivery systems.

Formulations within the scope of this invention include the admixture ofsPLA₂ inhibitor with a therapeutically effective amount of any of theco-agents as set out in the section “CO-AGENT—COMBINED THERAPY”, infra.For all of the above formulations the preferred active compound are the1H-indole-3-glyoxylamide compounds as previously described and methodsof making as described in n U.S. Pat. No. 5,654,326 (the disclosure ofwhich is incorporated herein by reference). Preferred compounds withinthe general class of 1H-indole-3-glyoxylamides have been described inpreceding sections of this specification.

Proportion and Weight of Active Compounds Used in the Method of theInvention

The 1H-indole-3-glyoxylamide compound may be used at a concentration of0.1 to 99.9 weight percent of the formulation.

Preferably the pharmaceutical formulation is in unit dosage form. Theunit dosage form can be a capsule or tablet itself, or the appropriatenumber of any of these. The quantity of active compound in a unit doseof composition may be varied or adjusted from about 0.1 to about 1000milligrams or more according to the particular treatment involved.

Compositions (dosage forms) suitable for internal administration containfrom about 1 milligram to about 500 milligrams of active compound perunit. In these pharmaceutical compositions the active compound willordinarily be present in an amount of about 0.5-95% by weight based onthe total weight of the composition.

Examples of useful pharmaceutical compositions and their proportions ofingredients are illustrated as follows:

Capsules: Capsules may be prepared by filling standard two-piece hardgelatin capsules each with 50 mg of powdered active compound, 175 mg oflactose, 24 mg of talc, and 6 mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active compound in soybean oil isprepared and injected by means of a positive displacement pump intogelatin to form soft gelatin capsules containing 50 mg of the activecompound. The capsules are washed in petroleum ether and dried.

Tablets: Tablets may be prepared by conventional procedures so that thedosage unit is 50 mg of active compound, 6 mg of magnesium stearate,70mg of microcrystalline cellulose, 11 mg of cornstarch, and 225 mg oflactose. Appropriate coatings may be applied to increase palatability ordelay absorption.

Suspensions: An aqueous suspension is prepared for oral administrationso that each 5 ml contain 25 mg of finely divided active compound, 200mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mg of vanillin.

Injectables: A parenteral composition suitable for administration byinjection is prepared by stirring 1.5% by weight of active compound in10% by volume propylene glycol and water. The solution is sterilized bycommonly used techniques.

Nasal Spray: An aqueous solution is prepared such that each 1 mlcontains 10 mg of active compound, 1.8 mg methylparaben, 0.2 mgpropylparaben and 10 mg methylcellulose. The solution is dispensed into1 ml vials. The active compound may be used at a concentration of 0.1 to99.9 weight percent of the formulation.

The Practice of the Method of the Invention

The method of the invention may be practiced using pharmaceuticalformulations containing sPLA₂ inhibitors (preferably, sPLA₂ inhibitorstaught to be preferred in this specification) or formulations containingsuch sPLA₂ inhibitors as taught in the preceding section.

Treatment of non-rheumatoid arthritis in a human may be therapeutic byadministering an sPLA₂ inhibitor to treat an existing condition so as tomitigate the effects of that event. Alternatively, treatment ofnon-rheumatoid arthritis in a human may be prophylactic by administeringan sPLA₂ inhibitor in anticipation of a worsening condition ofnon-rheumatoid arthritis, for example, in a patient whose occupation,lifestyle, or exposure to irritants will expectedly worsen an existingcondition of said non-rheumatoid arthritis. In some cases the underlyingcause of the disease state will not be prevented or cured, but may bereduced in severity or extent and its symptoms ameliorated byadministration of sPLA₂ inhibitors (and their formulations) using themethod of the invention.

The dosage administered will, of course, vary depending upon knownfactors such as the pharmacodynamic characteristics of the particularagent, and its mode and route of administration; age, health, and weightof the recipient; nature and extent of symptoms, kind of concurrenttreatment, frequency of treatment, and the effect desired. Usually adaily dosage of active compound can be about 0.1 to 200 milligrams perkilogram of body weight. Ordinarily 0.5 to 50, and preferably 1 to 25milligrams per kilogram per day given in divided doses 1 to 6 times aday or in sustained release form is effective to obtain desired results.

In general, the sPLA₂ inhibitor will be administered to a mammal such asman so that a therapeutically effective amount is received. Atherapeutically effective amount may coventionally be determined for anindividual patient by administering the active compound in increasingdoses and observing the effect on the patient, for example, reduction ofsymptoms associated with the particular non-rheumatoid arthriticcondition. Generally, the compound must be administered in a manner anda dose to achieve in the human a blood level concentration of sPLA₂inhibitor of from 10 to 3000 nanograms/ml, and preferably aconcentration of 100 to 800 nanograms/ml.

For patients with acute or non-rheumatoid arthritis, the treatmentregimen may stretch over many days to months or to years. Oral dosing ispreferred for patient convenience and tolerance. With oral dosing, oneto four oral doses per day, each from about 0.01 to 25 mg/kg of bodyweight with preferred doses being from about 0.1 mg/kg to about 2 mg/kg.

Parenteral administration (intravenous or intraarticular) is oftenpreferred in instances where rapid alleviation of patient distress isrequired. With parenteral administration doses of 0.01 to 100 mg/kg/dayadministered continuously or intermittently throughout the day may beused. For parenteral administation, the comound may be administered in aphysiologic saline vehicle (e.g., 0.9% normal saline, 0.45% normalsaline, etc.) a dextrose vehicle (e.g., 5% dextrose in water), or acombination of saline and dextrose vehicle (0.9% normal saline in 5%dextrose).

Inhalation therapy also may be useful either alone or as an adjunct toother routes of administration. With inhalation therapy, doses necessaryto produce a decrease in the clinical symptoms of non-rheumatoidarthritis are readily determined and used.

In accordance with the present invention, non-rheumatoid arthritis, andespecially osteoarthritis, is effectively treated by administering tothe afflicted subject a therapeutically effective amount of sPLA₂inhibitor. The administration of sPLA₂ inhibitor in accordance with thepresent invention can be accomplished either orally, topically, orparenterally. Depending upon the mode of application, various carrierscan be employed to facilitate transport of the sPLA₂ inhibitor into thesubject's body. For example, the sPLA₂ inhibitor can be administeredorally or injected to the afflicted area or topically in a carrier whichis absorbed through the skin such as dimethyl sulfoxide.

Co-Agent—Combined Therapy

The sPLA₂ inhibitor (viz., active compound in a formulation of theinvention) can also be administered in the method of the invention incombination with another pharmacologically active agent. For example,osteoarthritis is characterized by pain in the afflicted joints.Consequently, it is also advantageous to administer the active compoundtogether with an analgesic or other pain killer medication. Suitableco-agents as follows:

a. acetaminophen and ibuprofen

b. non-steroidal anti-inflammatory drugs, (NSAIDSs) prostaglandins(e.g., choline magnesium salicylate, salicylsalicyclic acid).

c. corticosteroids (e.g., methylprednisone, prednisone, cortisone).

Osteoarthritis is also characteriazed by over-activity of mitrixmetalloproteinase enzymes. Therefore, it is also advantageous topractice the method of the invention by co-administering the sPLA₂inhibitor with a mitrix metalloproteinase inhibitor.

It is also advantageous to practice the method of the invention byco-administering the sPLA₂ inhibitor with an inhibitor ofpro-inflammatory cytokines (e.g., anti-TNF molecules, TNF solublereceptors, and IL1RA.

Testing Methods for Non-Rheumatiod Arthritis

The diagnostic criteria for non-rheumatoid arthritis are those found instandard medical references (e.g., Harrison's Principles of InternalMedicine, thirteenth ed., 1994, by McGraw-Hill, Inc., ISBN0-07-032370-4). These criteria may be used to determine when to beginusing the method of the invention, the frequency and degree oftreatment, and the time for cessation of treatment. For osteoarthritis(OA) criteria are currently based on the clinical and obligatoryradiographic signs (Altman, R. D., J. F. Fries, D. A. Bloch et al. 1987Arthritis Rheum 30:1214-1225). Since the radiological diagnosis isusually based on a decreased joint space, it depends on actualdestruction of joint cartilage and may be made late in the disease.

In particular, for osteoarthritis:

Early Stage

Characterized by deep aching pain in joints and pain with motion,morning stiffness of short duration and variable joint thickening andeffusion.

Late Stage

Characterized by deep aching pain in joints with predominance of pain atrest accentuated on weight bearing joints and joint instability.

Treatment by the method of the invention is aimed at relief of pain (atrest and with motion), relief of stiffness, effusions, prevention ofbone damage, prevention of joint instability.

The time for initiating and ending treatment of a mammal using themethod of the invention may be accomplished using the followingNon-Rheumatoid Arthritis Assay Method.

The compounds of the invention may be evaluated by the following AssayMethod using the (WOMAC) Osteoarthritis Index VA3.0 procedure as theprimary indicator. This Assay Method is particularly applicable foracute and chronic treatment of signs and symptoms of osteoarthritis andis also applicable for other non-rheumatoid arthritis disease state.When necessary, non-rheumatoid arthritis disease states other thanosteoarthritis may be assayed using the applicable Secondary ClinicalTrial Endpoints set out below.

Primary Clinical Trial Endpoint

The primary clinical trial endpoint is the Western Ontario and McMasterUniversities (WOMAC) Osteoarthritis Index VA3.0. The VA3.0 indicatesthat the visual analog version of the WOMAC will be used rather than theLikert version. The WOMAC consists of 24 components (5 pain, 2stiffness, 17 physical function).

Western Ontario and McMaster Universities (WOMAC)

Osteoarthritis (OA) Index VA3.0

Pain

1. Walking on a flat surface

2. Going up or down stairs

3. At night while in bed

4. Sitting or lying

5. Standing upright

Stiffness

1. Morning stiffness

2. Gelling

Physical Function

1. Descending stairs

2. Ascending stairs

3. Rising from sitting

4. Standing

5. Bending to floor

6. Walking on flat

7. Getting in/out of car

8. Going shopping

9. Putting on socks/stockings

10. Rising from bed

11. Taking off socks/stockings

12. Lying in bed

13. Getting in/out of bath

14. Sitting

15. Getting on/off toilet

16. Heavy domestic duties

17. Light domestic duties

Bellamy et al. J Rheumatol 1988.

References to be Used to Size the Study are

Bellamy N. J Rheum 19:153- , 1992. Voltaren vs. meclo

Bellamy N. J Rheum 20:999- , 1993.

Bellamy N. J Rheum 19:451- , 1992. Setting the delta for clinicaltrials.

Bellamy N. J Rheum 19:444- , 1992. Calculating sample sizes for clinicaltrials.

Bellamy N. WOMAC User's Guide.

Reference to be Used for Validation of WOMAC is

Bellamy N. J Rheum 15:1833-1840, 1988

Validation Study of WOMAC

Secondary Clinical Trial Endpoints

I. WOMAC 3.0VA pain subscale

II. WOMAC 3.0VA physical function subscale

III. Patient global assessment

IV. Physician global assessment

V. WOMAC 3.0VA stiffness subscale

VI. Joint tenderness score

VII. Lequesne index (Lequesne et al. Scand J Rheumatol 1987)

VIII. Flares

IX. Physical signs including knee range of motion

X. Pain on passive motion of knee

XI. Synovial effusion (graded either as 0, 1, 2 or 3 or absent/present)

XII. Time required to walk 50 feet (seconds)

XIII.Tablet count of rescue medications (e.g. acetaminophen)

XIV. Biologic markers

A. serum sPLA₂ enzyme activity

B. serum sPLA₂ enzyme concentration (as measured by immunoreactivity)

C. serum sPLA₂ inhibitor drug concentrations

D. C-reactive protein

E. erythrocyte sedimentation rate (Westergren method)

F. plasma levels of 11-deoxythromboxane B2

Baseline Information to be Collected for Hip Osteoarthritis

radiographic severity of osteoarthritis on bilateral hip and knee X-raysaccording to Kellgren Lawrence criteria

Grade Criteria 0 normal I doubtful narrowing of joint space and possibleosteophytic lipping II definite osteophytes and possible narrowing ofjoint space III moderate multiple osteophytes and definite narrowing ofjoint space IV large osteophytes, marked narrowing of joint space,severe sclerosis, and definite deformity of bony contour

Kellgren J H, Lawrence J S. Radiological assessment of osteoarthritis.Ann Rheum Dis 16:494-501, 1957.

joint space width at the narrowest point (mm) and osteophyte number andsize on joint X-ray. A 1 mm deviation from a normal joint contour is anosteophyte.

joint groups involved

surgical procedures including arthroscopy

history of joint injury and joints involved

prior use of prescription medications including intra-articular agents(corticosteroids or hyaluronate). The patient will be provided with alist of possible medications.

physiotherapy including assistive devices (e.g., elevated toilet seat,tub seat, hand rails, elevating cushion for chair, pickup devices, sockpuller)

Steinbrocker functional class (0, I, II, III or IV)

patient global assessment score

physician global assessment score

While the present invention has been illustrated above by certainspecific embodiments, these are not intended to limit the scope of theinvention as described in the appended claims.

I claim:
 1. A method for treatment of a human afflicted withosteoarthritis, said method comprising administering to said human inneed of such treatment, a therapeutically effective amount of a1H-indole-3-glyoxylamide compound or a pharmaceutically acceptable salt,solvate, or a prodrug derivative thereof selected from the groupconsisting of compounds (A) through (P): (A)[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid, (B)dl-2-[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]propanoicacid, (C)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]aceticacid, (D)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-3-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]aceticacid, (E)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-4-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]aceticacid, (F)[[3-(2-Amino-1,2-dioxoethyl)-1-[(2,6-dichlorophenyl)methyl-]-2-methyl-1H-indol-4-yl]oxy]aceticacid (G)[[3-(2-Amino-1,2-dioxoethyl)-1-[4(-fluorophenyl)methyl-]-2-methyl-1H-indol-4-yl]oxy]aceticacid, (H)[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-[(1-naphthalenyl)methyl-]1H-indol-4-yl]oxy]aceticacid, (I)[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid, (J)[[3-(2-Amino-1,2-dioxoethyl)-1-[(3-chlorophenyl)methyl-]-2-ethyl-1H-indol-4-yl]oxy]aceticacid, (K)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-ethyl-1H-indol-4-yl]oxy]aceticacid, (L)[[3-(2-amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]aceticacid, (M)[[3-(2-Amino-1,2-dioxoethyl)-2-cyclopropyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid, (N)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-cyclopropyl-1H-indol-4-yl]oxy]aceticacid, (O)4-[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoicacid, and (P) mixtures of (A) through (O).
 2. The method of claim 1wherein said sPLA₂ inhibitor is administered orally.
 3. The method ofclaim 1 wherein said sPLA₂ inhibitor is administered parenterally.
 4. Amethod for treatment of a human currently afflicted with osteoarthritis,said method comprising administering to said human in need of suchtreatment a therapeutically effective amount of a1H-indole-3-glyoxylamide compound represented by the formulae:


5. A method for treatment of a mammal to alleviate or prophylacticallytreat osteoarthritis, said method comprising administering to saidmammal a therapeutically effective amount of[[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid, methyl ester.
 6. The method of claim 1 or 2 or 3 or 4 or 5 whereinthe administration is intravenous.
 7. The method of claim 1 or 2 or 3 or4 or 5 wherein the administration is oral.
 8. The method of claim 1 or 2or 3 or 4 or 5 wherein administration is in an amount of from 0.01mg/kg/day to 100 mg/kg/day.
 9. The method of claim 1 or 2 or 3 or 4 or 5wherein the therapeutically effective amount is in the form of apharmaceutical formulation comprising the compound and a suitablecarrier or excipient therefor.
 10. The method of claim 4 wherein theadministration is intravenous.
 11. The method of claim 4 wherein theadministration is oral.
 12. The method of claim 4 wherein treatment isof a mammal afflicted with a non-rheumatoid arthritis and the inhibitoris administered in a therapeutically effective amount to achieve a humanblood level inhibitor concentration of from 10 to 3000 nanograms/ml.